GENETIC CONTROL OF SEGMENTATION
J Susan
Kansas State Universitycity: Manhattan country: United States (us)
Grant 3R01HD029594-17S1 from Office Of The Director, National Institutes Of Health
Abstract: This award is issued in response to Notice OD-09-060, Recovery Act Administrative Supplements Providing Summer Research Experiences for Students and Science Educators. The clock and wavefront mechanisms underlying segmentation in vertebrates and the genetic hierarchy regulating segmentation in Drosophila seemingly imply independent origins of metameric development. However, comparative studies in non-drosophilid insects and other arthropods provide increasing molecular evidence for a common ancestry. In Drosophila, segments are patterned simultaneously. In most other insects including the red flour beetle Tribolium castaneum, other arthropods and vertebrates, segmentation is a longer process that occurs progressively from anterior to posterior. To understand the molecular mechanisms driving sequential metamerism and identify new genes important to this process, we are studying the genetic regulation of segmentation in Tribolium. In Tribolium, abdominal segments arise from a posterior growth zone during germband elongation, and RNAi with several early patterning genes truncates segmentation from the growth zone, suggesting this is an important regulation point. We have identified a gene circuit of primary pair-rule genes that functions to generate segments sequentially. Defects in its components disrupt the gene circuit and truncate the segmentation process. Periodic expression of two genes in this circuit initiates as twin spots in the posterior growth zone and may be regulated by early patterning genes. In addition, we have found that TcWnt8 is expressed in twin spots in the posterior growth zone, and TcWnt8 RNAi embryos are truncated in the thorax. We hypothesize that segmentation and elongation may be regulated by posterior signals that control components of the pair-rule gene circuit and/or proliferation. We will combine genetic and molecular approaches to analyze the relationship of cell proliferation, convergent extension and posterior signaling to segmentation, all of which are fundamental to embryonic elongation in vertebrates and arthropods. The genetic and genomic tools we have developed, combined with the Tribolium genome sequence, provide a unique opportunity to identify, regulatory genes and molecular processes which may represent presently unrecognized, developmentally significant mammalian counterparts important to segmentation. Our studies have the potential to provide new insight into human birth defects in spinal development and cancers related to misregulation of signaling mechanisms
Keywords: Abdomen; Anterior; Arthropods; Automobile Driving; Cell division; cell motility; Cell Polarity; Cell Proliferation; Chest; Comparative Study; Congenital Abnormality; Defect; Development; Drosophila genus; Embryo; Fibroblast Growth Factor; Flour; gene function; Genes; Genetic; genome sequencing; Genomics; Growth; Homologous Gene; Human; Insecta; insight; Lead; Ligands; Malignant Neoplasms; MAPK8 gene; Mediator of activation protein; Messenger RNA; Modeling; Molecular; Molecular Genetics; Notch Signaling Pathway; Nuclear; overexpression; Pathway interactions; Pattern; Positioning Attribute; Process; programs; Regulation; Regulator Genes; Research Personnel; RNA Interference; Role; Screening procedure; Signal Pathway; Signal Transduction; Spinal; Spottings; Surveys; tool; Transcriptional Activation; Tribolium (beetle); Twin Multiple Birth; Vertebrates
Project start date: 2009-06-01
Project end date: 2009-10-31
Budget start date: 1-JUN-2009
Budget end date: 31-OCT-2009
3R01HD029594-17S1 (2009): $47336
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to J Susan
THE ROLE OF GESTURE IN LEARNING
J Susan
University Of Chicagocity: Chicago country: United States (us)
Grant 5R01HD047450-08 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: When children talk, they gesture and these gestures serve as an index of the child´s readiness-to-learn. Work during the current grant period has shown that gesture does more than reflect thought--it plays a role in changing thought and, as a result, contributes to the learning process itself. The purpose of the proposed research is to explore the mechanism underlying this effect--specifically, whether gesture´s impact on learning stems, at least in part, from its grounding in action and, if so, whether educators can capitalize on gesture´s closeness to action to promote learning. The research has four aims. (1) To explore whether gesture and action work equally well to promote learning, Studies 1-4 manipulate whether children experience action (e.g., rotating an object) or gesture for that action (e.g., gesturing rotate) during training, and observe the effect of that manipulation on learning. (2) To explore whether gesture´s closeness to action affects how well it promotes learning, Studies 5-8 manipulate whether children experience concrete gesture (e.g., rotate with the hand shaped as though it were actually moving the object) vs. gesture (e.g., rotate with a pointing handshape) during training, and observe the effect of that manipulation on learning. (3) To explore whether concrete gesture serves as a stepping-stone to thinking, Studies 9-12 manipulate the order in which children experience concrete and gestures, and observe the effect of the manipulation on learning. (4) To explore whether gesture can hinder as well as help learning, Studies 13-16 provide children with gestures containing action features that are incompatible with the task, and observe the effect of incompatible gestures on learning. It is likely that the degree to which gesture resembles action has a larger or smaller effect on learning depending on the concreteness of the task to be learned. As a result, each series of studies uses two types of tasks--a task involving mental manipulation of concrete objects (mental rotation of parts of an object) and a task involving mental manipulation of symbolic objects (mathematical equivalence). In addition, because of the tight link between perceiving an action and performing the action, each series of studies varies whether the child produces gesture or action, or watches an experimenter produce gesture or action. Gesture is often used by children with impairments in language learning to compensate for their disabilities. Understanding the mechanism by which gesture promotes learning may be beneficial in both classroom and one-on-one tutorial situations, particularly in situations where acting directly on objects is not practical. The gestures that children produce when they talk not only reflect what they know, they can also change what children know and, in this way, play a role in the learning process. The proposed research explores whether gesture´s impact on learning stems from its grounding in action and, if so, whether educators can capitalize on gesture´s closeness to action to promote learning. Since children who have impairments in language often use gesture to compensate for their disabilities, emphasizing gesture may be particularly beneficial for children with special needs in both classrooms and one-on-one tutorial or assessment situations where it may not be practical for children to act
Keywords: ing; Acting Out; Affect; Attention; Calculi; Child; disability; Educational aspects; experience; Gestures; Grant; Hand; Health; Impairment; indexing; insight; Language; Language Development; Learning; Link; Mathematics; Movement; Outcome; Play; Process; Property; Psyche structure; Readiness; Reading; Research; Role; Rotation; Series; Shapes; Simulate; Speech; Staging; stem; success; Thinking, function; Training; Work
Relevance: The gestures that children produce when they talk not only reflect what they know, they can also change what children know and, in this way, play a role in the learning process. The proposed research explores whether gesture´s impact on learning stems from its grounding in action and, if so, whether educators can capitalize on gesture´s closeness to action to promote learning. Since children who have impairments in language often use gesture to compensate for their disabilities, emphasizing gesture may be particularly beneficial for children with special needs in both classrooms and one-on-one tutorial or assessment situations where it may not be practical for children to act
Project start date: 2004-07-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01HD047450-08 (2011): $332331
TARGETED AND GLOBAL PROTEOMIC STRATEGIES FOR EARLY BREAST CANCER DETECTION
J Susan
University Of California San Franciscocity: San Francisco country: United States (us)
Grant 5U24CA126477-07 from National Cancer Institute
Abstract: We propose to work cooperatively with other investigators funded by this U24 mechanism to evaluate proteomic technologies that will enable the early detection of several tumor types through the application of blood-based tests. Our group, consisting of scientists at LBNL, UCSF, The Buck Institute, MD Anderson Hospital, and the University of British Columbia, has the broad expertise that this project requires. We will focus on breast cancer. Initially, we will examine both global strategies and targeted mass spectrometry (MS)-based approaches to develop optimal workflows for the identification of protein signatures of human breast cancer cells in murine plasma. The global strategies will utilize multiple workflows that emphasize quantitative comparisons. The targeted approaches will focus on cancer-specific proteins that result from aberrant RNA splicing. Candidate biomarkers will be validated using reverse phase protein arrays. The requisite antibodies will be generated by Epitomics. The next phase of the project will employ human clinical samples. Specifically, we will apply an analogous, optimized approach for analyzing plasma samples that will be prospectively collected from breast cancer patients (n = 200). Control samples will be obtained from healthy women with benign breast disease and from women with rheumatoid arthritis to account for the contribution of proteins associated with inflammatory processes. Our candidate approach targets both the spliceome, which will be profiled using breast cancer biopsies from the plasma donors, and posttranslational modifications (e.g., glycosylation, phosphorylation, proteolysis and oxidative damage). We also include a plan for establishing a systematic way to standardize proteomic protocols and data analysis among the groups that exploits curability to analyze mass spectra generated on numerous platforms and the robust statistical methods we will employ to mine these large data sets. Several other elements of the RFA are also addressed. For example, we summarize the analysis capacity of our instruments and our strategy for sharing project-generated resources including biological specimens, protocols, data, software tools, and intellectual resources. In the end, we envision that our group, in conjunction with the other CPTAC teams and the NCI, will develop methods, tools and reference samples for the research community that will make the promise of MS-based cancer biomarker discovery a reality
Keywords: Accounting; Address; Antibodies; base; Benign; Biological; biomarker; Biopsy; Blood; Breast Cancer Cell; Breast Cancer Early Detection; Breast Diseases; British Columbia; Cancer Patient; Clinical; Communities; Data; Data Analyses; Data Set; Early Diagnosis; Elements; Funding; glycosylation; Human; Inflammatory; Institutes; instrument; malignant breast neoplasm; Malignant Neoplasms; Mass Spectrum Analysis; Methods; Mining; Mus; oxidative damage; Phase; Phosphorylation; Plasma; Post-Translational Protein Processing; Process; Protein Array; Proteins; Proteolysis; Proteomics; Protocols documentation; Research; Research Personnel; Resources; Rheumatoid Arthritis; RNA Splicing; Sampling; Scientist; Software Tools; Specimen; Statistical Methods; Technology; Testing; tool; tumor; University Hospitals; Woman; Work
Project start date: 2006-09-28
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-CA-07-012
5U24CA126477-07 (2011): $1091701
FUNCTIONAL GLYCOMICS OF HUMAN SALIVA
J Susan
University Of California San Franciscocity: San Francisco country: United States (us)
Grant 1R01DE021041-01A1 from National Institute Of Dental & Craniofacial Research
Abstract: We propose a functional glycomics analysis of human parotid and submandibular/sublingual salivas collected as the ductal secretions. A great deal is known about the salivary proteome. In contrast, the salivary glycome has received considerably less attention. This is a significant omission because saliva contains an unusually high proportion of glycoproteins with very unusual carbohydrate structures. These oligosaccharides have large numbers of sugars with complex branching patterns that are decorated with blood group determinants (e.g., ABO and Lewis families) and sulfate substituents. We think that this complexity encodes a great deal of biological information. For example, our previous studies suggest that these glycans play many interesting roles in cell adhesion. In this context, we propose testing the hypothesis that salivary glycans mediate essential functions, thereby exerting major influences on health and disease. To test this theory, we will use the accumulated expertise of our group in mass spectrometry-based carbohydrate structural analyses and in "omic-type" studies of human saliva. We have also developed a suite of assays for studying the functions of salivary oligosaccharides in terms of their adhesive interactions with bacteria and/or immune cells. Accordingly, we propose two specific aims. The goal of Aim 1 is a glycomic analysis of human parotid and submandibular salivas. Specifically, we will use several separation strategies to fractionate salivary components based on their glycan structures. Our approach includes capture by immobilized lectins and antibodies, which recognize specific aspects of oligosaccharide structure including linkage positions and anomeric/isomeric configurations. Our recent work demonstrates the utility of these approaches for significantly expanding the depth of glycomic analyses. Then we will use a variety of mass spectrometry-based platforms, including newly developed ion mobility separation approaches, to elucidate the structures of the fractionated glycans. We will also sequence their peptide attachment sites, which will allow us to delve deeper into the salivary proteome. In Aim 2, we will establish structure-function relationships in terms of adhesive interactions between salivary glycans and bacteria or immune cells, thereby increasing our understanding of the mechanisms that specify the oral ecology. The approaches we will employ include, as important variables, levels of shear stress that mimic the environment in the oral cavity. In summary, the data from these experiments will provide a comprehensive overview of the oligosaccharide structures that comprise the salivary glycome and their functions in terms of coordinating cell adhesion. We think that this important information could have several interesting clinical applications. For example, glycan profiles, so-called "glycotypes," are emerging as useful predictors of an individual´s risk of developing caries. Additionally, competitive inhibitors could be used to disrupt the adhesion of disease-related organisms and, conversely, oligosaccharide sequences that support adhesion of beneficial species could be used to improve the oral ecology. The goal of the proposed work is to use mass spectrometry-based methods to characterize the oligosaccharide structures that comprise the human salivary glycome and to assess their functions in terms of mediating bacterial and/or immune cell adhesion. These structure-function correlations will provide us important insights into the molecular mechanisms that establish the oral ecology of healthy individuals. In the aggregate, the resulting data will form a baseline against which disease-related changes can be measured, the long-term goal of this work
Keywords: Adhesions; Adhesives; Affinity; Alternative Splicing; Antibodies; Attention; Bacteria; base; Biological; Biological Assay; Biological Process; biomarker; Blood groups; Blood typing procedure; carbohydrate structure; Carbohydrates; Cell Adhesion; Cells; clinical application; clinically relevant; combinatorial; Complex; Data; Dental caries; design; Disease; Drosophila melanogaster; Ductal; Ecology; Environment; Enzymes; Equilibrium; Family; Fingerprint; Future; Genes; genome sequencing; Genotype; Glycopeptides; Glycoproteins; glycosylation; glycosyltransferase; Goals; Health; high throughput analysis; Human; human disease; Human Genome; Immune; improved; Individual; Information Theory; inhibitor/antagonist; Inorganic Sulfates; insight; interest; International; ion mobility; Lead; Lectin; Leukocytes; Mass Spectrum Analysis; Measures; Mediating; Methods; mimetics; Molecular; National Institute of Dental and Craniofacial Research; novel; Oligosaccharides; Oral; Oral cavity; Oral health; Organism; Parotid Gland; pathogen; Pathology; Pathway interactions; Pattern; Peptides; Phenotype; Play; Polysaccharides; Positioning Attribute; Post-Translational Protein Processing; Process; Protein Glycosylation; Proteins; Proteolysis; Proteome; Proteomics; public health relevance; Publishing; Research; Research Design; research study; Risk; Risk Assessment; Role; Saliva; Salivary; Salivary Proteins; Sampling; Series; shear stress; Signal Transduction; Site; Specific qualifier value; Structure; Structure-Activity Relationship; sugar; sugar nucleotide; Testing; theories; therapeutic target; Tissues; trafficking; translational study; treatment planning; Unspecified or Sulfate Ion Sulfates; Vertebral column; Work
Relevance: The goal of the proposed work is to use mass spectrometry-based methods to characterize the oligosaccharide structures that comprise the human salivary glycome and to assess their functions in terms of mediating bacterial and/or immune cell adhesion. These structure-function correlations will provide us important insights into the molecular mechanisms that establish the oral ecology of healthy individuals. In the aggregate, the resulting data will form a baseline against which disease-related changes can be measured, the long-term goal of this work
Project start date: 2011-04-01
Project end date: 2016-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-10-067
1R01DE021041-01A1 (2011): $386250
GENETIC CONTROL OF SEGMENTATION
J Susan
Kansas State Universitycity: Manhattan country: United States (us)
Grant 5R01HD029594-15 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Through comparative studies between distantly related animals, it has become apparent that genes and regulatory networks functioning during embryonic growth are highly conserved. This has led to the hypothesis that evolutionary changes in morphology can be traced to alterations in these regulatory modules. Studies to address this hypothesis have focused on insects, which display different modes of segmentation. Most approaches rely on cloning and expression analysis of orthologs of well-characterized Drosophila genes. However, most insects do not offer facile approaches to examine the functional significance of conserved gene expression patterns, or to test observed differences. Further, these comparisons are limited to the analysis of mechanisms discovered in flies, and do not offer the possibility of identifying genes important to segmentation in species other than flies. Our studies in Tribolium overcome these limitations, since Tribolium offers the possibility of genetic manipulation in addition to its facility for developmental and molecular studies. Moreover, the recent advances in RNA interference and germline transformation place Tribolium in the forefront of comparative model systems. We have discovered that depletion of certain pair-rule gene mRNAs by RNAi blocks segmentation and morphogenesis in Tribolium, results not predicted by the Drosophila paradigm. To understand the molecular interaction underlying these novel phenotypes we will examine the effects of Tceve and Tcrun mRNA depletion on the expression of other segmentation and homeotic genes. Analysis of the regulatory regions associated with these genes and ectopic expression of transgenes will complement the RNAi studies. To discover other genes important to segmentation in Tribolium we will execute a transposon-tagging mutagenesis scheme and characterize relevant mutants. Our research provides a unique opportunity to elucidate the genetic mechanisms underlying the regulation of the process of progressive segmentation in a cellular environment
Keywords: body regions; Coleoptera; cytogenetics; developmental genetics; early embryonic stage; embryogenesis; gene expression; gene interaction; gene mutation; genetic library; genetic manipulation; genetic mapping; genetic regulation; homeobox genes; in situ hybridization; molecular cloning; polymerase chain reaction; protein structure function; regulatory gene; southern blotting; species difference; western blottings
Project start date: 1992-08-01
Project end date: 2007-08-02
Budget start date: 1-AUG-2006
Budget end date: 2-AUG-2007
5R01HD029594-15 (2006): $287714
COLLABORATIVE APPROACHES TO THE STUDY OF INTESTINAL EPITHELIAL STEM CELLS
J Susan, Professor Of Medicine
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Grant 3U01DK085547-03S1 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: This proposal is submitted in response to an RFA for an intestinal stem cell (ISC) Consortium. As noted in the RFA, although the existence of stem cells in the small intestinal epithelium has been known for decades, there are currently no published methods to isolate pure preparations of these cells. In 2005 our group (1) used flow cytometric side population (SP) sorting to isolate for the first time a fraction enriched in ISCs as judged by enrichment for Musashi-1 mRNA (at that time the only known marker of ISCs). Subsequent microarray, in situ hybridization and resection (2; 3) studies have strengthened the evidence that SP cells from mouse small intestine include the ISCs. Although we empahsized from the outset (1) that the SP is not a pure ISC prepartion, better approaches to isolate ISCs from normal mouse or human small intestine have not yet been reported. In addition, to date proof of stemness with SP cells (or any other isolated cell fraction from the small intestine) has been hampered by lack of functional assays to demonstrate self-renewal and multi-lineage differentiation. Recent reports on new markers for ISC suggest that there may be active and quiescent subpopulations. However these have not yet been isolated and little is known about the the behavior of these two cell populations and cells expressing other ISC markers during intestinal development. To address these significant gaps we propose a collaborative approach which combines experts in intestinal development, stem cell isolation, surgical models of intestinal growth, genetics of stem cells and mouse models with altered signaling of key intestinal growth factors. Specifically, we propose the following aims 1. To improve isolation methods for ISC by the identification of suitable membrane antigens for antibody-based sorting and to use functional properties to separate active and quiescent ISC; 2. To develop in vivo assays to functionally validate self-renewal and multi-lineage differentiation of putative ISC preparations using three novel approaches; and 3. To characterize ISC behavior during intestinal development and to create a developmental tissue bank of small intestine for localization of known or novel ISC markers by other Consortium members. We believe that achievement of these goals is feasible. Understanding the biology of intestinal stem cells is central to the development of regenerative medicine approaches to various disorders in which intestinal function is compromised. For example expanding the pool of residual stem cells would be an ideal way to prevent or treat intestinal failure and short gut syndrome. Moreover, in situations where the stem cells themselves are damaged (e.g. after radiation or chemotherapy), transplantation of healthy stem cells may afford a novel and effective therapy
Keywords: Achievement; Address; analog; Antibodies; Antigens; base; Behavior; Biological Assay; Biology; blind; cell behavior; Cell Fraction; Cell membrane; cell preparation; Cell Separation; Cells; chemotherapy; Development; Disease; Doxorubicin; effective therapy; Epithelial; Excision; Failure (biologic function); Flow Cytometry; Genetic; Goals; Growth; Growth Factor; Histocompatibility Testing; Human; improved; In Situ Hybridization; in vivo; intestinal epithelium; Intestines; Label; LacZ Genes; Magnetism; member; Membrane; Messenger RNA; Methods; Modeling; mouse model; Mus; novel; novel marker; novel strategies; Population; postnatal; Preparation; prevent; Principal Investigator; Property; public health relevance; Publishing; Radiation; Regenerative Medicine; Reporting; Residual state; response; scaffold; self-renewal; Short Bowel Syndrome; Side; Signal Transduction; Small Intestines; Sorting - Cell Movement; stem; Stem cells; stemness; subcutaneous; Surgical Models; Thymidine; Time; Tissue Banking; Tissue Banks; Transplantation
Project start date: 2009-09-30
Project end date: 2014-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-DK-08-010
3U01DK085547-03S1 (2011): $130691
3U01DK085547-03S2 (2011): $17859
TRAINING PROGRAM IN CELL AND MOLECULAR BIOLOGY
J Susan, Prof, Molecular Virology & Microbiogy
Baylor College Of Medicinecity: Houston country: United States (us)
Grant 5T32GM008231-22 from National Institute Of General Medical Sciences
Abstract: This is the fourth competing renewal of the sole training grant supporting an interdepartmental graduate Program in Cell and Molecular Biology (CMB Program) at Baylor College of Medicine. The mission of the CMB Program is to train a new generation of PhD scientists who will become independent investigators and future leaders of interdisciplinary cell and molecular biology research to improve human health. The CMB Program was founded on a commitment to excellence in research, with strict guidelines for both student and faculty participation. The Program involves over 90 faculty from eight basic science departments, and four clinical departments, providing a dynamic mix of established investigators and newly recruited young faculty. Thus, our students can select from a wide spectrum of exciting research possibilities. During the 20 years of funding, 179 students have entered the program. PhD degrees have been awarded to 79 students, 13 received Master´s degrees, 29 withdrew or transferred, and 58 students are currently enrolled. We have been very successful in attracting students of high caliber to the College, through active recruitment mechanisms. As a consequence, the entering class size over the past eight years has been 9 to 12 students per year. The CMB Program emphasizes a rigorous graduate education program, and provides intensive mentoring through all stages of CMB graduate training. Correspondingly, the research productivity of our students has been exceptional, as measured by both the number and quality of CMB student-authored publications. The 28 students who graduated from the Program between 2005 and the present have published, on average, four papers resulting from their thesis research, including two first author papers, with an average impact factor of 9.22 per publication. An additional notable achievement during the last funding period has been our continued success in both recruiting, and retaining, underrepresented minority (URM) students, with 18 URM students (31%) currently enrolled in the program. In addition, our current URM CMB students include some of the top students in the College with regard to academic achievements. During the previous training period, 10 predoctorai positions were funded through this award. We are requesting an increase to 12 funded positions in the current renewal, which should maintain an enrolled student body of ~60 students, an optimal size for scientific interactions and mentoring by Program faculty. RELEVANCE Human health and the development of more effective approaches to treat human disease are major goals of our society. The CMB Training Program will train the next generation of PhD scientists to become leaders in the fight against human disease through cell and molecular biology research
Keywords: Cellular biology; Molecular Biology; Training Programs
Project start date: 1990-07-01
Project end date: 2015-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-08-226
5T32GM008231-22 (2011): $377730
CELL ISOLATION AND DIFFERENTIATION
J Susan
University Of California San Franciscocity: San Francisco country: United States (us)
Abstract: This Core will provide key support in the form of primary cells and cell lines that are integral to accomplishing the goals of every project in this U-54 application. The creation of this core acknowledges the fact that highly specialized technical skills are required to obtain the cell types with which we are working. Thus, we propose taking advantage of the unique combination of cell culture expertise in the Fisher and Reijo-Pera groups to support the work of all the participating investigators equally; i.e., 20% effort will be allocated to each project. The cells will come from two sources. The first is human placentas. Specifically, this tissue will be used for the isolation of highly purified preparations of primary cytotrophoblasts (CTBs) as well as villus explants. The second source of cells is mouse embryos, which will be used for the derivation of embryonic and trophoblast stem cells. In addition, quality control will be an important part of the Core´s activities. For example, we will use cytokeratin expression, a unique feature of CTBs in human placental cell preparations, to document purity. We will also analyze the cells´ ability to differentiate in vitro by monitoring the expression of stage-specific antigens that are upregulated with acquisition of an invasive phenotype (e.g., HLA-G). The quality of the mouse cells will be determined by assessing the differentiative capacity of control lines that are derived in parallel to study functional aberrations that appear as the result of genetic or experimental manipulations. Our specific plans for utilization of these cells are as follows. Control and mutant mouse embryonic stem cells will be provided to Project I with the goal of testing the hypothesis that gamete formation requires dazl function. Studies of the role of Notch family members in the initial stages of placentation will employ purified CTBs and villus explants (Project II). Likewise, experiments that are designed to identify the effect of endometrial stromal signals on CTB differentiation/invasion will also use human placental cells (Project III). Pilot Project I will utilize mouse trophoblast stem cells to understand the impact of in vitro fertilization on the differentiative capacity of these cells. Pilot Project II will also use mouse trophoblast stem cells, with the goal of determining the role of microRNAs in regulating cell fate decisions in the extraembryonic lineages. Because the availability of high-quality cells is a crucial requirement of every project, we envision the activities of this Core to be central to the success of this U-54 program
Keywords: Antigens; Biological; Cell Culture Techniques; Cell Differentiation process; Cell Line; cell preparation; Cell Separation; cell type; Cells; Communities; Cytokeratin; cytotrophoblast; Derivation procedure; design; Embryo; embryonic stem cell; Endometrial; Family member; Fertilization in Vitro; Genetic; Germ Cells; Goals; HLA G antigen; Human; In Vitro; Infertility; interest; MicroRNAs; Monitor; Mus; Mutant Strains Mice; notch protein; operation; Phenotype; Pilot Projects; Placenta; Placentation; Preparation; programs; Quality Control; Reproductive Biology; Research Personnel; research study; Role; Services; Signal Transduction; skills; Source; Staging; Stem cells; success; Testing; Tissues; trophoblast; Villus; Work
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5U54HD055764-05_9001 (2011): $224701
PLACENTAL ORIGINS OF PREECLAMPSIA: A GLOBAL ANALYSIS OF CYTROPHOBLAST ...
J Susan
Magee-women´s Res Inst And Foundationcity: Pittsburgh country: United States (us)
Abstract: The placenta is a transient organ with remarkable functions. Differentiation of its specialized epithelial cells, termed cytotrophoblasts (CTBs), is an important determinant of both its form and function. Our focus is the pathway that gives rise to the invasive subpopulation of cells. During interstitial invasion, a subset of CTBs commingles with resident decidual and immune cells. During endovascular invasion, these fetal cells invade the maternal blood vessels, which they subsequently line. Together, these two components of CTB invasion anchor the placenta to the uterus and divert uterine blood flow to the intervillous space. Given the complexities involved in this explosive process, it is not surprising that anomalies sometimes occur. Preeclampsia (PE), a syndrome that adversely affects the mother (by altering vascular function) and the fetus (by restricting intrauterine growth), is a prime example. Interstitial and endovascular invasion is shallow, and fewer spiral arteries are modified in toto. Our long-term goal is to elucidate the molecular bases of the placental defects that occur in PE and to explain their relationship to the clinical signs of this syndrome. Previously, we showed that in normal pregnancy CTB invasion is accompanied by a phenotypic switch in which these ectodermal derivatives take on many characteristics of endothelial cells. PE is associated with specific deficits in this program as evidenced by defects in adhesion molecule switching and perturbations in their production of angiogenic substances. Recently, we used an unbiased microarray approach to identify novel pathways that function within the basal plate region where the placenta attaches to the decidua. First, we studied the effects of advancing gestational age on gene expression in this area and then we examined the impact of PE. The results of these experiments revealed a wealth of new information. For example, consistent with the hypotheses to be tested in this program project, lipid pathways are among the most highly modulated in both analyses. In addition, molecules with known patterns of regulation (e.g., CRH in normal pregnancy; leptin and sFlt-1 in PE), were expressed in the expected manner, data that strengthen the importance of our novel findings. Accordingly, we now propose using a microarray approach to analyze the effects of PE on CTB invasion. Specifically, we will isolate the progenitors from affected and control placentas and compare their patterns of gene expression as they differentiate/invade in vitro (Aim 1). Then we will determine the functional significance of the changes we observe (Aim 2). We think that these experiments will yield fundamental new insights into the basic placental defects that lead to PE. Additionally", the results could also have clinical utility in prediction and/or diagnosis of this pregnancy complication, with the identification of potential therapeutic targets another possibility
Keywords: Affect; Angiogenic Factor; Appearance; Area; Basal Plate; base; Basement membrane; Blood; Blood flow; Blood Vessels; Cell Adhesion Molecules; Cells; Characteristics; Chorionic villi; Clinical; clinical application; CRH gene; cytotrophoblast; Data; Decidua; Defect; Development; Diagnosis; Endothelial Cells; Equus caballus; Etiology; Family member; Fetal Growth; Fetal Growth Retardation; Fetus; fetus cell; Funding; Gene Expression; Gestational Age; Goals; Hormones; Immune; In Vitro; Inflammation; insight; interstitial; Invaded; Lead; Leptin; Link; Lipids; Maternal-Fetal Exchange; Mesenchymal; Molecular; Molecular Genetics; Mothers; Myometrial; Names; Nature; novel; Obesity; Organ; Pathway interactions; Patients; Pattern; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Labor; Process; Production; progenitor; programs; receptor; Regulation; research study; Site; Specialized Epithelial Cell; Spiral Artery of the Endometrium; Stem cells; Surface; Syncytiotrophoblast; Syndrome; Techniques; Testing; therapeutic target; trophoblast; Uterus; Vascular Endothelial Growth Factors; Villous; Villus; Work
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5P01HD030367-17_0014 (2011): $210037
MOLECULAR MECHANISMS OF PLASMODIUM FALCIPARUM ADHERENCE TO THE HUMAN PLACENTA
J Susan
University Of California San Franciscocity: San Francisco country: United States (us)
Grant 5R21AI079329-02 from National Institute Of Allergy And Infectious Diseases
Abstract: The majority of pregnant women in malaria-endemic regions contract placental malaria (PM) at some point during gestation. PM is a severe form of malaria, leading to maternal complications and negatively affecting the survival and growth of the fetus. PM is defined as (1) the accumulation of Plasmodium falciparum-infected red blood cells (iRBCs) in the maternal blood spaces of the placenta, and (2) the cytoadherence of iRBCs to placental cells, such as syncytiotrophoblasts (STBs) that cover the chorionic villi and face the intervillous space where maternal blood circulates. One mechanism for iRBC cytoadherence to host receptors is through PfEMP1 proteins, encoded by parasite var genes and expressed on the surface of iRBCs in a mutually exclusive manner. With respect to placental receptors, chondroitin sulfate A (CS-A) has been consistently implicated in iRBC cytoadhesion. The physiological relevance of other purported receptors remains controversial, and most PM researchers agree that additional placental receptors remain to be described. Some gaps in knowledge remain. First, investigators have primarily focused on identifying receptors expressed by term placentas and have not considered the relationship between this tissue and iRBCs during early gestation. Second, they have only studied the involvement of the intervillous space in supporting cytoadhesion, completely ignoring the basal plate region of the placenta. Whether iRBCs cytoadhere to early gestation tissue and whether they cytoadhere to cells in the basal plate remain open questions that we are currently exploring with primary human placental tissue. We first reviewed the expression of putative receptors in early gestation tissue, both in the intervillous space and the basal plate. In the intervillous space, our results suggest that CS-A may not be involved in the initial stages of placental infection because we did not detect this antigen on the STB covering that is in contact with maternal blood. In the basal plate, our results reveal that cytotrophoblasts (CTBs) in contact with maternal blood express ICAM-1, a well-characterized receptor for iRBCs in non-pregnant individuals. We hypothesize that iRBC cytoadhesion may involve specific molecules that are uniquely expressed in both the intervillous space and the basal plate by early gestation human placental cells, including STBs and CTBs that are in direct contact with maternal blood. We will test this hypothesis with the following experiments. First (Aim 1), we will identify molecules that are spatially and temporally positioned to play a role in early gestation iRBC cytoadhesion. Next (Aim 2), we will functionally determine if these molecules act as early gestation placental receptors for iRBCs. Finally (Aim 3), we will identify cognate parasite-encoded ligands involved in cytoadhesion. At the conclusion of these experiments, we will have substantially advanced our understanding of the molecular interactions between iRBCs and the human placenta. Our proposed work will establish experimental systems for studying PM throughout human gestation and aid the malaria field in identifying potential drug and vaccine targets for treating this condition. The results of the proposed experiments will substantially advance our understanding of the ligand-receptor molecular interactions between Plasmodium falciparum-infected red blood cells (iRBCs) and early gestation human placental tissue. As part of our proposed experiments, we will develop novel experimental models that will be useful to other researchers interested in studying placental malaria throughout human gestation. Our proposed work will realistically aid the malaria field in identifying potential drug and vaccine targets
Keywords: Adherence (attribute); Adhesives; Affect; Animal Model; Antigens; Basal Plate; Binding (Molecular Function); Blood; Blood capillaries; Blood flow; capillary; Cells; Chondroitin Sulfate A; Chorionic villi; Contracts; cytotrophoblast; Data; Detection; Developmental Process; Epidemiology; Equation; Erythrocytes; Experimental Models; Face; fetal; Fetal Growth Retardation; Fetus; Figs - dietary; Gene Expression; Genes; Gestational Age; Growth; Human; Human body; Immune system; Individual; Infection; insight; Intercellular adhesion molecule 1; interest; Invaded; Knowledge; Lead; Ligands; Low Birth Weight Infant; Malaria; Mediating; Molecular; novel; Organ; parasite genome; Parasites; Pharmaceutical Preparations; Physiological; Placenta; Placentation; Plasmodium falciparum; Play; Positioning Attribute; Pregnancy; pregnant; Pregnant Women; premature; Premature Birth; Proteins; public health relevance; receptor; Reporting; Research Personnel; research study; Role; Side; Spontaneous abortion; Staging; Stillbirth; Structure; Surface; Syncytiotrophoblast; System; Testing; Tissues; Vaccines; venule; Work
Relevance: The results of the proposed experiments will substantially advance our understanding of the ligand-receptor molecular interactions between Plasmodium falciparum-infected red blood cells (iRBCs) and early gestation human placental tissue. As part of our proposed experiments, we will develop novel experimental models that will be useful to other researchers interested in studying placental malaria throughout human gestation. Our proposed work will realistically aid the malaria field in identifying potential drug and vaccine targets
Project start date: 2009-05-07
Project end date: 2012-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2012
PFA/PA: PA-06-181
5R21AI079329-02 (2010): $181502
Sponsored Links Excellgen http://Excellgen.com
SPECIMEN RESOURCES AND PATHOLOGY CORE
J Susan
Emory Universitycity: Atlanta country: United States (us)
Abstract: The goal of the Specimen Resources and Pathology Core (SPRC) is to provide superior technical expertise to the investigators on this proposal. Experienced head and neck pathologists and cytopathologists will work closely with each SPORE project as well as the Biostatistics and Administrative Cores to ensure efficient and highly-coordinated procurement, archiving, and storage of human tissue samples. Continuous communication between the clinicians, scientists, research nurses, biostatisticians, and pathologists together with established standardized operating procedures for all core activities will provide optimal tissue collection and accurate processing, analysis, and storage of each sample. The SRPC will function as the main repository of patient specimens and will oversee specimen processing and histopathology. This Core will utilize and expand the already well-established tissue banking efforts at Emory University for translational research. Histopathologic analysis by the Core pathologists will confirm the quality and presence of the expected study tissue in research specimens. Selected cellular biomarkers will be explored using immunohistochemistry. These immunostains will be interpreted by core pathologists. Cytology specimens will be generated, and cytopathologic support in processing and interpreting the specimens will be provided. In addition, animal study specimen processing, histopathology, immunohistochemistry, and pathologic interpretive support will be provided. Taken together, the primary objectives of the Specimen Resources and Pathology Core are to 1) Facilitate the acquisition, preservation, analysis, and dispersal of clinical samples 2) Provide accurate histopathological and cytological characterization of head and neck tissues for all project investigators, thus providing uniform quality assurance 3) Identify oral dyplasia biopsy specimens in the Oral, Head and Neck Biopsy service 4) Offer reliable centralized laboratory services to the SPORE investigators with respect to tissue samples that include histochemistry, immunohistochemical staining, in-situ hybridization, and laser capture microdissection By assisting the researchers in these translational projects, we hope to advance the understanding of how oral cancer develops and aid in the development of treatment and preventive stategies for oral cancer
Keywords: Animals; Archives; Biological Preservation; biomarker; Biometry; Biopsy; Biopsy Specimen; Clinical; Communication; Cytology; Ensure; experience; Goals; Head and Neck Cancer; Head and neck structure; Histocytochemistry; Histopathology; human tissue; Immunohistochemistry; In Situ Hybridization; Laboratories; laser capture microdissection; malignant mouth neoplasm; Nursing Research; Oral; Pathologic; Pathologist; Pathology; Patients; Preventive; Procedures; Process; quality assurance; repository; Reproduction spores; Research Personnel; Resources; Sampling; Scientist; Services; Specimen; Specimen Handling; Staining method; Stains; Technical Expertise; therapy development; Tissue Banking; Tissue Banks; Tissue Sample; Tissues; Translational Research; Universities; Work
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P50CA128613-05_9001 (2011): $288611
SMOOTH MUSCLE MECHANISMS IN DYNAMIC AIRWAY PROPERTIES
J Susan
Indiana Univ-purdue Univ At Indianapoliscity: Indianapolis country: United States (us)
Grant 5R01HL029289-25 from National Heart, Lung, And Blood Institute
Abstract: The effects of stretch and oscillation on airway smooth muscle that occur normally during breathing are important in maintaining a normal low level of airway reactivity. The plasticity of the cytoskeletal structure of the airway smooth muscle cell may be fundamental to its ability to modulate its contractile and mechanical properties in response to the mechanical forces imposed on it in the lung. Integrin-linked kinase (ILK) is a multidomain (1-integrin-cytoplasmic domain binding protein and a functional serine-threonine protein kinase that associates with ( integrins and other cytoskeletal proteins at adhesion sites. The ILK protein complex is positioned to regulate structural links between integrin proteins and the actin cytoskeleton and to coordinate signaling pathways that regulate cytoskeletal functions. ILK has also been identified as a pivotal effecter in the transduction of signals from integrin proteins and the extracellular matrix to the nucleus. The proposed studies will evaluate the role of the ILK protein complex in regulating cytoskeletal organization and functional responses to the contractile stimulation of airway smooth muscle. The role of ILK in regulating the phenotype of airway smooth muscle will also be determined. Endogenous and recombinant protein expression will be manipulated in isolated tracheal smooth muscle tissues by transfecting tissues with plasmids encoding mutant forms of ILK and its binding partners and downstream effectors. The specific aims are 1) Determine whether the contractile stimulation of airway smooth muscle regulates the formation of an integrin-linked kinase (ILK) protein complex associated with sites of integrin adhesion to the extracellular matrix, and evaluate the function of this complex in the regulation of active tension generation. 2) Evaluate the effect of contractile stimulation on the kinase activity of ILK, and determine the role of ILK kinase activity in the regulation of tension development in airway smooth muscle. 3) Evaluate the role of the integrin-linked kinase protein complex in the regulation of protein synthesis and the expression of phenotypic proteins in airway smooth muscle tissues. The results will provide new information on the molecular mechanisms by which hormones and environmental stimuli regulate the structure and contractile responses of airway smooth muscle. This information will be important for understanding the pathogenesis of inflammatory diseases of the airways such as asthma
Keywords: Actins; Adhesions; airway smooth muscle; Aspiration, Respiratory; Asthma; Binding; Binding (Molecular Function); Binding Proteins; biological signal transduction; Biosynthetic Proteins; Body Tissues; Breathing; Bronchial Asthma; Cell Communication and Signaling; cell growth; Cell Locomotion; Cell Migration; cell motility; Cell Movement; Cell Nucleus; Cell Signaling; Cell Surface Receptors; cell type; Cell-Extracellular Matrix; Cellular Expansion; Cellular Growth; Cellular Matrix; Cellular Migration; Chemotherapy-Hormones/Steroids; Complex; Couples; Cytoplasmic Domain; Cytoplasmic Tail; Cytoskeletal Modeling; Cytoskeletal Organization; Cytoskeletal Organization Process; Cytoskeletal Proteins; Cytoskeletal Reorganization; Cytoskeletal System; Cytoskeleton; Development; Disease; disease/disorder; Disorder; Doctor of Philosophy; EC 2.7; ECM; Endocrine Gland Secretion; Environment; Extracellular Matrix; Extracellular Matrix Proteins; Extracellular Matrix, Integrins; Gene Expression; gene product; Generalized Growth; Generations; Growth; Hormones; ILK; Inflammatory; Inhalation; Inhaling; inspiration; Inspiration, Respiratory; integrin-linked kinase; Integrins; Intracellular Communication and Signaling; intracellular skeleton; Investigators; Kinases; Leiomyocyte; Ligand Binding Protein; Link; Lung; Mechanics; Mediating; Molecular; Molecular Interaction; Motility; Motility, Cellular; Muscarinic Acetylcholine Receptor; Muscle strain; Muscle, Involuntary; Muscle, Smooth; mutant; Myocytes, Smooth Muscle; Nucleus; ontogeny; p59(ILK); Pathogenesis; Peptide Biosynthesis, Ribosomal; Ph.D.; PhD; Phenotype; Phosphotransferases; Plasmids; Play; polymerization; Position; Positioning Attribute; Property; Property, LOINC Axis 2; Protein Biosynthesis; Protein Biosynthesis, Ribosomal; protein complex; protein expression; protein synthesis; Protein Synthesis, Ribosomal; Protein-Serine Kinase; Protein-Serine-Threonine Kinases; Protein-Threonine Kinase; Proteins; pulmonary; receptor; Receptor Protein; Receptors, Muscarinic; Recombinant Proteins; Regulation; Research Personnel; Researchers; respiratory smooth muscle; Respiratory System, Lung; response; Role; Serine Kinase; Serine-Threonine Kinases; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Protein; Site; Smooth muscle (tissue); Smooth Muscle Cells; Smooth Muscle Myocytes; Smooth Muscle Tissue Cell; social role; Stimulus; Stretching; Structure; Therapeutic Hormone; Threonine Kinase; Tissue Growth; Tissues; Transcription Regulation; Transcriptional Control; Transcriptional Regulation; Transphosphorylases
Project start date: 1989-07-01
Project end date: 2012-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
5R01HL029289-25 (2011): $377500
J Susan
University Of California San Franciscocity: San Francisco country: United States (us)
Abstract: The Core Mass Spectrometry Facility (CMSF) is being proposed as a new Cancer Center shared resource. The CMSF is the successor to a prior UCSF mass spectrometry facility with which the Cancer Center cooperated for the past three years. The success of the cooperation and the increased need of members for mass spectrometry services has lead the Cancer Center to assume management of this facility. Effective provision of mass spectrometry services requires highly skilled personnel to provide effective guidance for non-expert investigators, and a substantial instrumentation base. The senior staff of the CMSF consists of a faculty director, a Ph.D. manager, and two faculty co-directors of operations, who also are P.l.s and/or investigators on competitively-funded research projects that develop and apply novel mass spectrometry techniques. These projects share use and support of the instrumentation, and assist with provision of funds for acquisition of advanced technology. This organizational structure assures timely availability of advanced mass spectrometry capability to Cancer Center members. The CMSF also benefits from cooperation with the substantial mass spectrometry efforts distributed´across the campus and at neighboring institutions, including nationally-prominent facilities and projects. The CMSF operates and maintains four mass spectrometers, four HPLC systems, two sample preparation robots at its main location, and has access to two additional mass spectrometers and an HPLC instrument at a satellite site. This instrumentation, along with an array of associated bioinformatics hardware and software enables the facility to offer a comprehensive suite of proteomic MS services to Cancer Center members. Representative services include multiple approaches to protein identification, quantitation, molecular mass determination, and data interpretation. In addition, consultation with regard to experimental design, sample preparation, data publication and grant writing are provided. The CMSF has a strong commitment to educating its users. Several different venues enable this process including seminars, training classes, and electronic mailings, which keep users abreast of the latest developments in sample preparation, MS technology, instrumental design and labeling chemistries as well as basic MS principles
Keywords: Area; base; Bioinformatics; Biological; Breast; Cancer Center; Cancer Center Support Grant; Chemistry; Clinical; Collaborations; Complex; Comprehensive Cancer Center; Computer software; Consultations; Cutaneous; Data; design; Development; Doctor of Philosophy; Educational aspects; Electronic Mail; Electronics; Equipment; experience; Experimental Designs; Faculty; Funding; Grant; High Pressure Liquid Chromatography; Human Resources; Immunity; Institutes; Institution; instrument; instrumentation; interest; Label; Laboratories; Lead; lectures; Location; Malignant neoplasm of prostate; Malignant Neoplasms; mass spectrometer; Mass Spectrum Analysis; meetings; member; molecular mass; Molecular Structure; novel; oncology; operation; organizational structure; Participant; pre-doctoral; Preparation; Principal Investigator; Process; programs; Proteins; Proteomics; Publications; Research; research and development; Research Personnel; Research Project Grants; research study; Resource Sharing; Resources; Robot; Sampling; Science; Services; Site; Structure; success; System; Techniques; Technology; Technology Assessment; Time; Training; Universities; Work; Writing
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
5P30CA082103-13_9016 (2011): $123620
GENETIC CONTROL OF SEGMENTATION
J Susan
Kansas State Universitycity: Manhattan country: United States (us)
Grant 5R01HD029594-20 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: The clock and wavefront mechanisms underlying segmentation in vertebrates and the genetic hierarchy regulating segmentation in Drosophila seemingly imply independent origins of metameric development. However, comparative studies in non-drosophilid insects and other arthropods provide increasing molecular evidence for a common ancestry. In Drosophila, segments are patterned simultaneously. In most other insects including the red flour beetle Tribolium castaneum, other arthropods and vertebrates, segmentation is a longer process that occurs progressively from anterior to posterior. To understand the molecular mechanisms driving sequential metamerism and identify new genes important to this process, we are studying the genetic regulation of segmentation in Tribolium. In Tribolium, abdominal segments arise from a posterior growth zone during germband elongation, and RNAi with several early patterning genes truncates segmentation from the growth zone, suggesting this is an important regulation point. We have identified a gene circuit of primary pair-rule genes that functions to generate segments sequentially. Defects in its components disrupt the gene circuit and truncate the segmentation process. Periodic expression of two genes in this circuit initiates as twin spots in the posterior growth zone and may be regulated by early patterning genes. In addition, we have found that TcWnt8 is expressed in twin spots in the posterior growth zone, and TcWnt8 RNAi embryos are truncated in the thorax. We hypothesize that segmentation and elongation may be regulated by posterior signals that control components of the pair-rule gene circuit and/or proliferation. We will combine genetic and molecular approaches to analyze the relationship of cell proliferation, convergent extension and posterior signaling to segmentation, all of which are fundamental to embryonic elongation in vertebrates and arthropods. The genetic and genomic tools we have developed, combined with the Tribolium genome sequence, provide a unique opportunity to identify, regulatory genes and molecular processes which may represent presently unrecognized, developmentally significant mammalian counterparts important to segmentation. Our studies have the potential to provide new insight into human birth defects in spinal development and cancers related to misregulation of signaling mechanisms
Keywords: Abdomen; Anterior; Arthropods; Automobile Driving; Cell division; cell motility; Cell Polarity; Cell Proliferation; Chest; Comparative Study; Congenital Abnormality; Defect; Development; Drosophila genus; Embryo; Fibroblast Growth Factor; Flour; gene function; Genes; Genetic; genome sequencing; Genomics; Growth; Homologous Gene; Human; Insecta; insight; Lead; Ligands; Malignant Neoplasms; MAPK8 gene; Mediator of activation protein; Messenger RNA; Modeling; Molecular; Molecular Genetics; Notch Signaling Pathway; Nuclear; overexpression; Pathway interactions; Pattern; Positioning Attribute; Process; programs; Regulation; Regulator Genes; Research Personnel; RNA Interference; Role; Screening procedure; Signal Pathway; Signal Transduction; Spinal; Spottings; Surveys; tool; Transcriptional Activation; Tribolium (beetle); Twin Multiple Birth; Vertebrates
Project start date: 1992-08-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5R01HD029594-20 (2011): $260068
5R01HD029594-19 (2010): $270904
5R01HD029594-18 (2009): $273641
5R01HD029594-17 (2008): $273641
2R01HD029594-16 (2007): $279225
ANALYTIC TECHNIQUES AND TECHNOLOGY
J Susan, Distinguished Professor
University Of Kansas Lawrencecity: Lawrence country: United States (us)
Abstract: The Analytic Techniques and Technology Core (AT&T) is a reconfigured core designed to provide advanced data analytic services to Center investigators. It complements the functions of the Participant Recruitment and Management and Digital and Electrical Engineering Cores by concentrating on techniques and technologies for data analysis including the application of advanced statistical techniques. The Core assists Center investigators by (1) planning and conducting advanced statistical analyses using cutting-edge methods including mixed modeling, structural equation modeling, and other techniques for the analysis of multivariate, longitudinal data; (2) training Center investigators in innovative advanced analytic techniques such as graphical analysis and data warehousing; and (3) helping with grant proposal preparation and final report preparation including write-up of methods, procedures, and results sections. The AT&T Core provides Center investigators with the ability to use new methods, for the detection of individual and group differences in patterns of growth and change, enabling Center investigators to move forward on current research programs. The Core offers strategic, targeted, high-level services that are elsewhere. The AT&T Core brings Center researchers together for workshops and tutorials on new methods for the analysis of change and new technologies for data aggregation and analysis that serve as "incubators" for crossdisciplinary initiatives. A key new initiative for the AT&T Core is developing Center-level collaborations to compile a data warehouse of measures of language and cognitive development making it possible for Center investigators to use new techniques for aggregate analysis and graphical analysis to explore commonalties among their projects. A key question will be to examine the relationship between cognition, grammatical development and vocabulary development across the life span, with an aim to detecting, e.g., early life predictors or reading impairments in school-aged children or predictors of late life cognitive decline
Keywords: ing; Applications Grants; biobehavior; Child; Cognition; Cognitive; Collaborations; Communication impairment; Complement; Data; Data Aggregation; Data Analyses; design; Detection; Development; digital; Educational workshop; Elderly; Electrical Engineering; Equation; Growth; Impaired cognition; Impairment; Incubators; Individual; innovation; Institutes; Investigation; Language; Life; Longevity; Measures; meetings; Methods; Modeling; Multivariate Analysis; new technology; Participant; Pattern; Preparation; Procedures; programs; Psychology; Reading; Reporting; Research; Research Design; Research Infrastructure; Research Personnel; School-Age Population; Science; Services; statistical service; Structural Models; Techniques; technology/technique; Time; Training; Use of New Techniques; Vocabulary; Writing
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5P30DC005803-10_9005 (2011): $152715
THE ARCHITECTURE AND FUNCTION OF RNPS REQUIRED FOR RIBOSOME BIOGENESIS
J Susan, Associate Professor
Yale Universitycity: New Haven country: United States (us)
Grant 5R01GM052581-15 from National Institute Of General Medical Sciences
Abstract: Ribosomes, the cellular powerhouses of translation, are assembled from rRNA, the catalytic moiety, and scores of ribosomal proteins. In eukaryotic cells, the pre-rRNA undergoes extensive chemical modifications and several cleavage events as it is being assembled with ribosomal proteins into the small and large subunits of the ribosome. In the yeast, S. cerevisiae, progress over the last 15 years has revealed that these RNA processing events are mediated by numerous small nucleolar ribonucleoproteins (snoRNPs) and as many as 500 trans-acting protein and RNA-protein complexes. While by now most of the factors involved in making ribosomes have been identified, little is known about how they are assembled together to make the functional units of the pre-ribosome, and how each of these units contributes to specific events in gene expression. Our long-term goal is to understand the pre-rRNA processing, RNA folding and ribosome assembly steps essential to ribosome biogenesis in eukaryotic cells. The objective of this application is to determine the architecture and organization of some of the macromolecular assemblies involved in ribosome biogenesis in order to gain much needed mechanistic insights. The strong preliminary data that we have generated for each of these strategies indicates a high likelihood of success. The rationale for the proposed research is to attain an understanding of how the protein components of s(no)RNPs, RNPs and associated protein subcomplexes are assembled and how they interact with each other to mediate steps in ribosome biogenesis. For this study, we propose the following Specific Aims 1. To test the hypothesis that the archaeal box C/D sRNP assembles and functions as a di-sRNP; 2. To elucidate the architecture and organization of small RNPs and protein complexes involved in eukaryotic SSU ribosome biogenesis; 3. To test the hypothesis that the pre-rRNA processing machinery is assembled in an ordered, stepwise manner to elucidate how these large macromolecules function in ribosome biogenesis. The proposed work is innovative because we will use experimental strategies that have not yet been applied to the study of ribosome biogenesis, and because little is known about the architecture and assembly of these ubiquitous RNA-protein complexes. The results will be significant because ribosome biogenesis is a fundamental step in gene expression to which all cells, particularly growing ones, devote a significant amount of their metabolism. Dysregulation of ribosome biogenesis is linked to cancer in humans, and mutations in SSU processome proteins have been linked to neonatal cirrhosis, infertility and neurofibromatosis. This proposal is designed to answer important questions about the function and organization of protein and RNA-protein complexes that have been implicated in the pathogenesis of cancer and several rare human genetic diseases. A more thorough understanding of these processes will help us design better therapies for malignancies
Keywords: 1, 2, 3-Propanetriol; 1, 2, 3-Trihydroxypropane; Archaea; Archaebacteria; Archaeobacteria; Archaeon; Architecture; Biochemical; Biogenesis; Boxing; Cancers; Cannot achieve a pregnancy; Cell Nucleolus; Cells; Chemicals; Cirrhosis; Complex; D-Ribose; Data; design; designing; Difficulty conceiving; Electron Microscopy; Electrons; Engineering / Architecture; Eukaryote; Eukaryotic Cell; eukaryotida; Event; gel electrophoresis; Gene Expression; Gene Probes, RNA; gene product; Gene Products, RNA; Genetic; Genetic Alteration; Genetic Change; Genetic Condition; Genetic defect; Genetic Diseases; genetic disorder; genome mutation; Glycerin; Glycerol; Goals; Hereditary Disease; hereditary disorder; Human; Human Genetics; Human, General; in vivo; infertile; Infertility; innovate; innovation; innovative; insight; Intermediary Metabolism; Link; macromolecular assembly; macromolecule; malignancy; Malignant Neoplasms; Malignant Tumor; Man (Taxonomy); Man, Modern; Maps; Mediating; Metabolic Processes; Metabolism; METBL; Methylation; Microscopic; Modification; Molecular Disease; Multiple Neurofibromas; Mutation; Negative Beta Particle; Negatrons; Neonatal; neoplasm/cancer; Neurofibromatoses; Neurofibromatosis; Neurofibromatosis Syndrome; nucleolus; Origin of Life; particle; Pathogenesis; Plasmosome; Pre-rRNA; Process; protein complex; Protein Methylation; Proteins; public health relevance; reconstitute; reconstitution; Research; Ribonucleic Acid; ribonucleoprotein, U3 small nucleolar; Ribose; Ribosomal Proteins; Ribosomal RNA; Ribosomes; RNA; RNA Conformation; RNA Folding; RNA Metabolism[{..}] Processing and Transport; RNA Probes; RNA Processing; RNA, Non-Polyadenylated; RNA, Ribosomal, Precursors; rRNA; rRNA Precursor; S cerevisiae; Saccharomyces cerevisiae; Small Nucleolar Ribonucleoproteins; snoRNP; Structure; success; Testing; Time; Translations; Two Hybrid; U3 small nuclear ribonucleoprotein; U3 snoRNP; U3 snRNP; unable to bear children; Work; Yeast One Hybrid System; Yeast One/Two-Hybrid System; yeast two hybrid system; Yeast, Baker`s; Yeast, Brewer`s; Yeasts
Relevance: 7. This proposal is designed to answer important questions about the function and organization of protein and RNA-protein complexes that have been implicated in the pathogenesis of cancer and several rare human genetic diseases. A more thorough understanding of these processes will help us design better therapies for malignancies
Project start date: 1996-02-01
Project end date: 2014-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-070
5R01GM052581-15 (2011): $400143
Sponsored Links Excellgen http://Excellgen.com
3R01GM052581-15S1 (2011): $8795
J Susan
University Of Chicagocity: Chicago country: United States (us)
Abstract: Objectives. The objectives of the Administrative Core are two-fold (1) to provide coordination, logistical support, and financial accounting for all Cores and Research Projects; (2) to foster interactive activities and integrative research
Keywords: Accounting; Address; Administrative Personnel; Advisory Committees; Amendment; Applications Grants; Award; Behavioral; Biological; Biomedical Engineering; Brain; Brain imaging; Businesses; Charge; Chicago; Child; Code; Cognitive Science; Collaborations; Consult; cost; Critiques; Data; data management; Data Set; design; Development; Doctor of Medicine; Doctor of Philosophy; Documentation; Educational aspects; Ensure; Equipment and Supplies; Evaluation; Faculty; Feedback; Financial Support; Fostering; Funding; Genetic Transcription; Goals; graduate student; Grant; Growth; Health Policy; Home environment; Human Resources; human subject; human subject protection; Individual; injured; interest; Joints; Language; Language Development; Linguistics; literacy; Literature; Manuscripts; medical schools; meetings; member; Methods; Minority; Monitor; Neurology; Neurosciences; Online Systems; operation; Oral; Oregon; Paper; Participant; Pattern; payment; Pediatric Radiology; Pediatrics; Pennsylvania; Performance; Persons; Phase; Physicians; Physics; Play; Policies; Preparation; prevent; Procedures; Process; professor; Program Evaluation; programs; Protocols documentation; Psychology; public health medicine (field); Reading; Reading Disabilities; Records; Recruitment Activity; Report (account); Reporting; Research; Research Ethics Committees; Research Institute; Research Personnel; Research Project Grants; Resource Sharing; Role; Schedule; Schools; Scientist; Series; Services; sharing data; skills; Snow; Social Sciences; Solutions; Students; Time; Universities; Variant; Visit; Work
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5P01HD040605-09_9003 (2011): $232902
DATA COLLECTION AND TRANSCRIPTION
J Susan
University Of Chicagocity: Chicago country: United States (us)
Abstract: Objective. Core B has three goals to recruit participants for each of the four projects; to collect data for each of the four projects; and to transcribe the speech and gesture data gathered in Projects I, II and III
Keywords: Biological; Data; Data Collection; Genetic Transcription; Gestures; Goals; Grant; Growth; Language; Participant; Recruitment Activity; Services; Speech; Variant
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5P01HD040605-09_9002 (2011): $378576
REGULATION OF SYMPATHETIC NEURON SYNAPTIC ACTIVITY
J Susan, Associate Professor
Brandeis Universitycity: Waltham country: United States (us)
Grant 5R01NS066977-02 from National Institute Of Neurological Disorders And Stroke
Abstract: Neural control of the cardiac system depends on the opposing actions of the sympathetic and parasympathetic nervous systems. The sympathetic system is excitatory for beat rate and cardiac output, and dysregulation of sympathetic drive has been linked to a number of human disorders including hypertension and heart failure. The ability to devise new approaches for the treatment of these disorders requires an understanding of the mechanisms that control sympathetic output. These mechanisms take place at the level of sympathetic neurotransmission onto cardiac cells and the regulation of activity levels of ganglionic sympathetic neurons. While sympathetic neurons form excitatory noradrenergic synapses onto cardiac muscle cells, they are also able to synthesize and release acetylcholine, which acts as an inhibitory neurotransmitter for heart muscle and an excitatory neurotransmitter at synapses that the neurons form onto themselves. We will investigate the acute regulation of co- transmission in these neurons and determine the roles of the neurotrophic factors nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and their receptors, in coordinating local neurotransmitter properties at neuronal and cardiac synapses. We will use electrophysiology, immunocytochemistry, and perturbation experiments to determine the role of BDNF and NGF in modulating pre- and postsynaptic properties and to examine spatially restricted effects of neurotrophins at sympathetic synapses. We will determine if neurotrophins acutely modulate sympathetic function in vivo. Finally, we will investigate neurotrophic regulation of activity levels and firing properties and will determine how integration of intrinsic and synaptic regulation defines the functional output of the cardiac system. Heightened sympathetic drive to the heart is linked to a number of pathologies, including sudden cardiac death. In this project we will investigate mechanisms that acutely regulate the level of excitatory and inhibitory transmission in individual sympathetic neurons and test the hypothesis that interactions with target-derived neurotrophic factors can rapidly modulate the pattern of sympathetic activity and the effects of that activity on synaptic function. An understanding of these mechanisms will permit new approaches for developing therapeutics for cardiac pathologies
Keywords: 1, 2-Benzenediol, 4-(2-amino-1-hydroxyethyl)-, (R)-; 2-(Acetyloxy)-N, N, N-trimethylethanaminium; Acetylcholine; Acute; BDNF; biological signal transduction; Blood Pressure, High; Body Tissues; Brain-Derived Neurotrophic Factor; Cardiac; Cardiac Diseases; Cardiac Disorders; cardiac failure; cardiac muscle; Cardiac Myocytes; Cardiac Output; Cardiocyte; cardiomyocyte; Cardiovascular; Cardiovascular Body System; Cardiovascular system; Cardiovascular system (all sites); Cell Communication and Signaling; Cell Signaling; Cells; cholinergic; cholinergic neuron; circulatory system; Death, Sudden, Cardiac; Development; Disease; disease/disorder; Disorder; Electrophysiology; Electrophysiology (science); Ethanaminium, 2-(acetyloxy)-N, N, N-trimethyl-; experiment; experimental research; experimental study; Heart; Heart Diseases; heart disorder; Heart failure; heart muscle; Heart myocyte; heart output; Human; Human, General; hyperpiesia; hyperpiesis; Hypertension; hypertensive disease; immunocytochemistry; In Vitro; in vivo; Individual; Intracellular Communication and Signaling; Levarterenol; Levonorepinephrine; Link; Man (Taxonomy); Man, Modern; MGC34632; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Muscle Cells, Cardiac; Muscle Cells, Heart; Muscle, Cardiac; Muscle, Heart; Myocardium; Myocytes, Cardiac; Nerve Cells; Nerve Growth Factor Receptors; Nerve Growth Factors; Nerve Impulse Transmission; Nerve Transmission; Nerve Transmitter Substances; Nerve Unit; Nervous System; Nervous system structure; Neural Cell; neural circuit; neural circuitry; neural control; neural regulation; Neural Transmission; Neurocyte; Neurologic Body System; Neurologic Organ System; neuronal; Neuronal Transmission; Neuronotrophic Factors; Neurons; Neurophysiology / Electrophysiology; neuroregulation; neurotransmission; Neurotransmitters; neurotrophic factor; Neurotrophic Factor Receptor; Neurotrophic Factors; Neurotrophic Proteins; neurotrophin; Neurotrophins; neutrophin; new approaches; new therapeutics; next generation therapeutics; Noradrenaline; noradrenergic; Norepinephrine; novel approaches; novel strategies; novel strategy; novel therapeutics; NRVS-SYS; Organ System, Cardiovascular; Output; Parasympathetic Nervous System; Pathology; pathway; Pathway interactions; Pattern; Population; postsynaptic; presynaptic; Property; Property, LOINC Axis 2; public health relevance; receptor; Receptor Protein; Receptors, Nerve Growth Factor; Receptors, Neurotrophin; Receptors, NGF; Regulation; research study; response; Role; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Site; social role; synapse function; Synapses; Synaptic; synaptic function; Synaptic Transmission; System; System, LOINC Axis 4; Testing; Therapeutic; Tissues; Transmission; transmission process; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Vascular, Heart; Whole-Cell Recordings
Relevance: Heightened sympathetic drive to the heart is linked to a number of pathologies, including sudden cardiac death. In this project we will investigate mechanisms that acutely regulate the level of excitatory and inhibitory transmission in individual sympathetic neurons and test the hypothesis that interactions with target-derived neurotrophic factors can rapidly modulate the pattern of sympathetic activity and the effects of that activity on synaptic function. An understanding of these mechanisms will permit new approaches for developing therapeutics for cardiac pathologies
Project start date: 2010-02-01
Project end date: 2014-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-070
5R01NS066977-02 (2011): $300558
HUMAN TROPHOBLAST DIFFERENTIATION AND NOTCH SIGNALING
J Susan
University Of California San Franciscocity: San Francisco country: United States (us)
Abstract: In eutherian mammals, the placenta is the first functional organ. Our previous work highlights the unusual plasticity of the human organ´s specialized epithelial cells¿cytotrophoblasts (CTBs). For example, they mimic many aspects of endothelial cells (ECs) including their adhesion molecule repertoire and production of VEGF and Ang family members. Recently, we considered the possibility that CTB differentiation might involve mechanisms that regulate not only blood vessel (BV) formation, but more precisely arterial specification. The cell-cell interactions that occur as CTBs invade the uterine wall support this theory. CTBs breach the uterine BVs, thereby diverting maternal blood flow to the placenta. Subsequently, the cells form superficial connections with uterine veins. In contrast, they replace the EC lining of uterine spiral arterioles and intercalate within their muscular walls, a process that involves nearly the entire intrauterine course of these vessels. Thus, CTBs have the molecular machinery to preferentially colonize arteries. At a molecular level CTB progenitors within the placenta express EphB4, which is involved in venous specification. As the cells differentiate/invade they abruptly downregulate expression of this receptor and upregulate ephrinB2 required for arterial development. Accordingly, we examined CTB expression of Notch family members that play upstream regulatory roles in vascular development and arterial EC differentiation. We found that CTBs express a broad repertoire of these molecules and that inhibitors of Notch signaling impaired their invasion and ephrinB2 expression. Thus, we now propose experiments to test the hypothesis that Notch signaling plays a critical role in controlling CTB differentiation/invasion and the cells´ ability to form a functional arterial endothelium. Accordingly, the goal of Aim 1 is to perform a detailed analysis of CTB expression of Notch family members. In Aim 2, we will study the functions of molecules that are expressed in a manner that suggests important roles. Thus, at the conclusion of the proposed experiments we will know a great deal more about the unusual process of CTB transformation into EC-like cells, which we think will yield important new insights into mechanisms that are crucial to normal placentation and may be dysregulated in cases of infertility or poor pregnancy outcome. By collaborating with other investigators in this U-54 program, we expect to gain additional insights into these normal and disease processes in terms of trophoblast function
Keywords: Adhesives; Angiopoietins; Arteries; arteriole; base; Biological; Birth; Blood Circulation; Blood flow; Blood Vessels; Cell Adhesion Molecules; Cell Communication; Cell Differentiation process; Cell Line; cell type; Cells; Complex; cytotrophoblast; Data; Decidua; Development; Developmental Process; Disease; Embryo; Endothelial Cells; Endothelium; Eph Family Receptors; Ephrins; Epithelial; Family member; Gastrointestinal tract structure; Goals; Human; In Situ; in utero; Infertility; inhibitor/antagonist; insight; interest; interstitial; Invaded; jagged1 protein; L-Selectin; Leukocytes; Ligands; Mammals; Maternal-Fetal Exchange; Modeling; Molecular; molecular marker; Muscle; myometrium; Neuropilins; notch protein; Organ; Pathway interactions; Pattern; Phenocopy; Placenta; Placentation; Play; Pregnancy; Pregnancy Outcome; Process; Production; progenitor; Program Reviews; programs; Property; receptor expression; Research Personnel; research study; Respiratory physiology; Role; Side; Signal Transduction; Specialized Epithelial Cell; Structure; Structure of uterine vein; Testing; theories; tissue culture; trophoblast; Urinary system; Vascular Endothelial Growth Factors; Venous; Work
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5U54HD055764-05_0002 (2011): $68194
PROJECT 2 PHARMACOKINETICS AND PHARMACODYNAMICS OF C60 AND MWCNTS IN NON-PREGNANT
J Susan, Senior Scientist
Research Triangle Institutecity: Research Triangle Park country: United States (us)
Abstract: Important components in estimating risks associated with exposure to nanomaterials include understanding the uptake, distribution, and elimination; the mode of acfion; and the pharmacodynamics of the effects of nanoparticles. Pregnancy and lactation are physiological states in which the distribution and effects of nanomaterials have not been extensively invesfigated. This project will invesfigate the absorption, distribution, metabolism, and excrefion of several nanoparticles with different size and charge properties. Investigations will be conducted with fullerene 060 and forms of multi-walled carbon nanotubes in female rats and mice, pregnant rats and mice, and in lactating rats and mice. The nanoparticles will be carbon-14 uniformly labeled by the RTI Synthesis and Characterization Core for conduct of these studies. Using three different routes of administration in female rats and mice (oropharyngeal aspiration, oral gavage, and intravenous [i.v.] injection) will provide information regarding the uptake and distribution processes for nanoparticles. Administration of the labeled nanoparticles to pregnant rats and mice by i.v, injection at different times in pregnancy will provide information about the ability of the nanoparticles to cross the placenta and result in fetal exposure. Analogously, i.v. administration to lactating rats and mice will enable evaluation ofthe secretion of nanoparticles into milk, resulting in exposure to offspring. The determinafion of the mass balance of radiolabel in urine, feces, blood tissues, and carcass at 5 time points over a period of 30 days following dosing will provide an enhanced understanding of the long-term fate of nanoparticles in the body. Quantitative whole body autoradiography will enable detailed characterization of the distribution of the nanoparticles. Examination of tissue samples with transmission electron microscopy will provide information on the subcellular localization of the nanomaterials. The effects of exposure to the carbon nanomaterials by oropharyngeal aspiration and i.v. administration will be investigated in the non-pregnant and pregnant (i.v. only) rodent by measuring arterial vascular reactivity, blood pressure, and cardiac ultrasound. The determination of markers of inflammation (cytokines), reproduction and development (hormones), and oxidative stress (8-hydroxydeoxyguanosine; 8- OHdG) will be conducted. The data obtained from Project 2 will be used in the development ofthe physiologically based pharmacokinetic and pharmacodynamic models constructed in Project 3
Keywords: 8-hydroxy-2`-deoxyguanosine; absorption; ing; Adult; adverse outcome; Affect; analog; Animals; Arteries; Autoradiography; base; biomarker; Blood; Blood Circulation; Blood Pressure; Blood Vessels; C14 isotope; Carbon; Carbon nanoparticle; Cardiac; Cardiac Output; Cardiovascular Physiologic Processes; Cardiovascular system; cellular imaging; Charge; Colostrum; cytokine; Data; Defect; Deposition; Development; dosage; Dose; Drug Formulations; Drug Kinetics; Engineering; Equilibrium; Evaluation; Excretory function; Exposure to; Feces; Female; Fetus; fullerene C60; Fullerenes; Glass; Grant; Health; Hormones; Human; Immune system; In Vitro; in vivo; Inflammatory; inflammatory marker; Injection of therapeutic agent; Intravenous; intravenous administration; intravenous injection; Investigation; Iron; Label; Lactation; Learning; Life; Liquid substance; Lung; Measurement; Measures; Mesentery; Metabolic; Metabolism; Metals; Methods; Milk; Modeling; Modification; mouse model; multi walled carbon nanotube; Mus; nanomaterials; nanoparticle; Nanotubes; National Institute of Environmental Health Sciences; Neonatal; neonate; offspring; Oral; Oropharyngeal; Outcome; oxidation; oxidative damage; Oxidative Stress; Parents; particle; Perinatal Exposure; pharmacodynamic model; Pharmacodynamics; pharmacokinetic model; Phase; Physiological; Physiology; Placenta; Predisposition; Pregnancy; pregnant; Preparation; Procedures; Process; Production; Property; pup; Radioactivity; radioactivity analysis; Radiolabeled; radiotracer; Rattus; Reaction; Reproduction; reproductive; reproductive development; Reproductive system; Research; response; Risk; Risk Estimate; Rodent; Role; Route; Sampling; Scintillation Counting; Serum; Site; Staging; Suspension substance; Suspensions; Tail; Time; Tissue Sample; Tissues; Transmission Electron Microscopy; Tube; Ultrasonography; uptake; Urine; Veins; Work
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
5U19ES019525-02_5557 (2011): $443280
NEONATAL HYPXIA-ISCHEMIA INDUCED SEIZURES:DEVELOPMENT OF SEIZURE DETECTION ALGORI
J Susan, Research Director/ Research Professor
Weill Medical College Of Cornell Univcity: New York country: United States (us)
Grant 1R03NS071296-01A1 from National Institute Of Neurological Disorders And Stroke
Abstract: Hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal seizures. However, considerable controversy exists over the treatment of seizures in encephalopathic neonates. A major problem is the electroclinical dissociation or uncoupling observed in the neonatal population with infants displaying behaviors that mimic seizures without EEG documentation, or electro-encephalographic seizure activity without clear clinical manifestations (subclinical seizures), in addition to clinical seizures (reviewed in Silverstein and Jensen(1)). The impact of either of these seizure subtypes on longterm outcome, as well as whether and how to treat neonatal seizures, remain vital questions. To address questions such as these it is important to turn to our well-described animal models of hypoxic-ischemic injury to the immature brain. However, most studies to date have used chemicals to induce seizures in conjunction with hypoxia-ischemia (HI), potentially making them less relevant to the clinical situation. We have recently expanded our model of unilateral cerebral hypoxia-ischemia in the immature rat to include simultaneous video monitoring and EEG (VEEG) and EMG recording before, during, and following HI. We are able to record behavioral, EEG, and EMG changes induced by HI in the absence of any chemical seizure induction. Our preliminary studies suggest that HI induces seizure-like behaviors without corresponding EEG changes, subclinical seizures of EEG activity without activity, as well as clinical seizures, similar to that observed in both term and preterm infants. We have begun to correlate seizure pattern during and after HI with brain damage. However, it is clear that unbiased, quantitative methods are needed to detect and characterize the different seizure types accurately. We propose two Specific Aims 1) To analyze and expand existing data from the term-equivalent P12 rat pup to characterize and reliably detect seizure types; and 2) To apply the methods of Aim 1 to the more immature, near-term equivalent, P7, rat pup to test the hypothesis that the younger animals will have a greater number of subclinical seizures during and after HI. For both aims we propose that the accurate detection of all of these events will allow for correlation of seizure burden with outcome in individual animals. The experiments proposed here are appropriate to the R03 mechanism in that they will firmly establish this new methodology so that we can specifically address the important clinical/translational questions related to neonatal seizures in the context of hypoxic-ischemic encephalopathy. Perinatal asphyxial brain damage, or hypoxic-ischemic encephalopathy (HIE), is a major cause of acute mortality and chronic neurologic morbidity in infants and children. HIE is the most common cause of seizures in the neonatal period, yet there continues to be major clinical questions regarding accurate diagnosis of these seizures, especially in the absence of behavioral changes, and whether, and how, to treat them. Seizures in preterm infants due to hypoxia-ischemia (HI) may be different from those in term infants with HIE. Many animal studies addressing these questions employ chemical induction of seizures in addition to experimental hypoxia-ischemia. We have developed a model to study HI-induced neonatal seizures in the rat (both term- and preterm-equivalent) without chemical intervention. This research proposal will develop the quantitative methods necessary to detect and characterize the different seizure types accurately and objectively so that we will then be able to address the important translational/clinical questions
Keywords: Acute; Address; Adult; Algorithms; Animal Model; Animals; Antiepileptic Agents; Behavior; Behavioral; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cerebral Ischemia-Hypoxia; Characteristics; Chemicals; Child; Chronic; Clinical; Consensus; critical period; Data; Detection; Development; Diagnosis; Dissociation; Documentation; Electroencephalography; Evaluation; Event; Future; Gender; Goals; Hour; Hypoxia; Individual; Infant; Inflammation; Injury; Intervention; Ischemia; juvenile animal; Measurement; Methodology; Methods; Modeling; Monitor; Morbidity - disease rate; Mortality Vital Statistics; Neonatal; neonatal hypoxic-ischemic brain injury; neonate; Neurologic; Outcome; Pattern; Perinatal; Perinatal Hypoxia; Pharmaceutical Preparations; Physiological; Population; postnatal; Premature Infant; prototype; public health relevance; pup; Rattus; Reader; Recovery; Research Proposals; research study; response; Rodent; Seizures; Staging; Subclinical Seizures; Testing; Therapeutic Intervention; Time; Tissues
Relevance: Vannucci, Susan J. Perinatal asphyxial brain damage, or hypoxic-ischemic encephalopathy (HIE), is a major cause of acute mortality and chronic neurologic morbidity in infants and children. HIE is the most common cause of seizures in the neonatal period, yet there continues to be major clinical questions regarding accurate diagnosis of these seizures, especially in the absence of behavioral changes, and whether, and how, to treat them. Seizures in preterm infants due to hypoxia-ischemia (HI) may be different from those in term infants with HIE. Many animal studies addressing these questions employ chemical induction of seizures in addition to experimental hypoxia-ischemia. We have developed a model to study HI-induced neonatal seizures in the rat (both term- and preterm-equivalent) without chemical intervention. This research proposal will develop the quantitative methods necessary to detect and characterize the different seizure types accurately and objectively so that we will then be able to address the important translational/clinical questions
Project start date: 2011-04-01
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-10-064
1R03NS071296-01A1 (2011): $80967
THE IMMUNE PARADOX OF HUMAN PREGNANCY: FETAL TROPHOBLASTS AND MATERNAL LEUKOCYTES
J Susan
University Of California San Franciscocity: San Francisco country: United States (us)
Grant 5R21HD055638-02 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Human pregnancy sets up an inherent immunological paradox. In a tumor-like process, semi-allogeneic fetal cells of the placenta (cytotrophoblasts; CTBs) invade the uterine lining (decidua) where they reside amongst an unusual subpopulation of maternal immune cells termed decidual granular leukocytes (DGLs), which comprise approximately 40% of the cells in this location. About 30% of DGLs are T cells, dendritic cells and macrophages; the majority (70%) are natural killer (NK) cells. Purified uterine NK (uNK) cells, an unusual CD56brightCD16- population, exhibit reduced but not totally abrogated killing of target cell lines in vitro. Yet, during normal pregnancy, there is no evidence that they lyse CTBs in vivo. Whether uNK cells are capable of lysing primary CTBs in vitro remains an open question that we recently addressed. Specifically, we cultured either DGLs or purified uNK cells with CTBs. The results were dramatic. Consistent with previous findings from our group and other investigators, uNK cells in the context of the total leukocyte population failed to kill CTB targets. However, purified uNK cells quickly surrounded and lysed CTBs, to our knowledge, the first demonstration of this phenomenon. These results suggest a new two-part hypothesis (1) Specific receptors and ligands mediate uNK lysis of CTBs; and (2) Protection is normally afforded by regulatory cells that reside within the DGL population as a whole. Here we propose experiments that are designed to test this theory. First, we will characterize, in detail, the repertoire of receptors which uNK express that engage MHC class I proteins and other molecules. At the same time, we will profile CTB expression of candidate ligands, information that we will use to expand our list of potential uNK receptors. Second, the results of these experiments will allow us to perform co-culture assays to test the functions of receptors and ligands with expression patterns, which suggest that they are playing important roles. Third, we will identify the regulatory cells in the DGL population as a whole that inhibit uNK lysis of CTBs. Thus, at the conclusion of these experiments, we will have substantially advanced our understanding of the mechanisms that control maternal tolerance of fetal cells during human pregnancy. Beyond human reproduction, this study could impact the fields of NK cell biology and tolerance in general, providing novel strategies for preventing the rejection of transplanted cells and tissues. The results of the proposed experiments will substantially advance our understanding of the mechanisms that control maternal tolerance of fetal cells during human pregnancy. Beyond human reproduction, this study could impact the fields of NK cell biology and tolerance in general, providing novel strategies for preventing the rejection of transplanted cells and tissues
Keywords: Address; Allogenic; Assay; base; Basic Research; Basic Science; Bioassay; Biologic Assays; Biological Assay; Blood granulocytic cell; Blood leukocyte; Body Tissues; cell biology; Cell Function; Cell Line; Cell Lines, Strains; Cell physiology; Cell Process; Cell Transplants; CellLine; Cells; Cellular biology; Cellular Function; Cellular Physiology; Cellular Process; clinical care; Co-culture; Cocultivation; Coculture; Coculture Techniques; cultured cell line; Cytolysis; Cytotoxic cell; Cytotrophoblast; cytotrophoblast; Decidua; Decidua Graviditas; Dendritic Cells; design; designing; Development; Embryonic Tissue, Placenta; Exhibits; experiment; experimental research; experimental study; fetal; fetus cell; gene product; Genetic Polymorphism; Genital System, Female, Uterus; Gestation; Graft Rejection; Granular Leukocytes; granulocyte; Granulocytic cell; Hand; heavy metal lead; heavy metal Pb; Histocompatibility; HL-A Antigens; HLA Antigens; Human; Human Leukocyte Antigens; Human, General; Immune; In Vitro; in vivo; interest; Invaded; Investigators; K lymphocyte; Killings; Knowledge; language translation; Lead; Left; Leukocyte Antigens; Leukocytes; Ligands; Location; Lysis; macrophage; Man (Taxonomy); Man, Modern; Marrow leukocyte; Mediating; Microscopy, Video; Molecular; Natural Killer Cells; Nature; new approaches; NK Cells; novel approaches; novel strategies; novel strategy; Pattern; Pb element; Placenta; Placenta-Tissue, Cells; Placentoma, Normal; Placentome; Play; polymorphism; Polymorphism (Genetics); Polymorphism, Genetic; Population; Pregnancy; Pregnancy Complications; prevent; preventing; Process; Proteins; public health relevance; receptor; receptor function; Receptor Protein; Reproduction; Research Personnel; research study; Researchers; Reticuloendothelial System, Leukocytes; Reticuloendothelial System, Thymus; Role; social role; Structure of cytotrophoblast; Subcellular Process; T-Cells; T-Lymphocyte; Testing; theories; Thymus; thymus derived lymphocyte; Thymus Gland; Thymus Proper; Thymus-Dependent Lymphocytes; Time; Tissue Compatibility; Tissues; Translating; Translatings; Transplant Rejection; Transplantation Rejection; trophoblast; tumor; Uterus; Veiled Cells; Video Microscopy; Videomicrography; Videomicroscopy; white blood cell; White Blood Cells; white blood corpuscle; White Cell; womb
Project start date: 2008-08-01
Project end date: 2011-07-31
Budget start date: 1-AUG-2009
Budget end date: 31-JUL-2011
PFA/PA: PA-06-181
5R21HD055638-02 (2009): $187611
GESTURE IN VARYING ENVIRONMENTS:ITS ROLE IN REVEALING CHILD ABILITIES AND INFLUEN
J Susan
University Of Chicagocity: Chicago country: United States (us)
Abstract: From the very earliest stages of language learning, children gesture as they talk. In adults, gesture is integrated with the speech it accompanies, often conveying information that is related, but not identical, to the information conveyed in that speech. Gesture can thus expand a speaker´s communicative range. Project II builds on previously collected longitudinal obervations of 60 children, ages 14 months to school entry, whose families were chosen to represent the demographic range of Chicago. The project observes gesture in these children who will be followed as they enter school until age 10. In addition to providing normative gesture data for the brain injured children in Project III, Project II has three specific aims. (1) Given that gesture can serve as a window that is distinct from speech into the child´s communicative abilities during the early stages of language-learning, the first aim is to characterize the way gesture is used in later stages of language-learning as children begin school. Study 1 asks whether gesture continues to expand the children´s communicative repertoires in the later years, providing the first sign of more complex syntactic constructions and new discourse devices. (2) Given individual differences in how children use gesture during the early stages of language-learning, the second aim is to explore whether those differences predict later language use. Study 2 asks whether gesture not only opens the door for languagelearning but also sets the learning trajectory. (3) The third aim is to explore whether gesture plays a causal role in language-learning. Study 3 experimentally manipulates gesture in 144 additional 1-word speakers and observes the effect of this manipulation on their vocabulary and their transition to 2-word speech. While most children successfully acquire the language to which they are exposed, some achieve mastery later than others. The timing of each milestone may be important for its effect on the eventual outcome of language acquisition, as well as for its impact on other cognitive skills. Project II explores whether gesturing also varies, and, if so, how that variability is related to variability in later languagelearning. Given that there are individual differences in how often families use gesture, it becomes important to determine whether gesture plays a role in language-learning. If so, educators need to become aware of the skills children display in the nonverbal realm, and learn to use them to improve verbal skills
Keywords: 5 year old; Adult; Age; Biological; Brain; Chicago; Child; Child Language; Church; Cognitive; cohesion; Communication; Complex; cooking; Data; Development; Devices; Elements; Environment; Family; Gestures; Goals; Grant; Growth; Hand; improved; Individual Differences; injured; insight; Language; Language Development; Learning; Measures; Modeling; Outcome; Play; Research; Role; Schools; Semantics; skills; Sorting - Cell Movement; Speech; Staging; syntax; Testing; Thinking, function; Time; Variant; Vocabulary; Work
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5P01HD040605-09_0002 (2011): $145920
FROM SPONTANEOUS SIGN SYSTEMS TO SIGN LANGUAGE
J Susan
University Of Chicagocity: Chicago country: United States (us)
Grant 2R01DC000491-24 from National Institute On Deafness And Other Communication Disorders
Abstract: Deaf children whose hearing losses prevent them from accessing spoken language and whose hearing parents have not exposed them to sign language are effectively deprived of input from a conventional language. Despite their lack of linguistic input, these children develop gesture systems, called homesigns that have many of the properties of natural language. The fact that children can develop certain linguistic properties under relatively impoverished language learning circumstances provides strong evidence for the resilience of these properties. But homesign does not exhibit all of the properties of natural language. The goal of the proposed research is to explore the conditions under which homesign becomes a full-blown language. Deaf children rarely remain homesigners in the US; they either learn a conventional sign language or receive cochlear implants and focus on spoken language. In Nicaragua not only do some homesigners continue to use their gesture systems into adulthood, but 30 years ago large numbers of homesigning children were brought together for the first time and Nicaraguan Sign Language (NSL) was born. NSL has continued to develop as new waves of children enter the community and learn to sign from older peers. The first generation, taken together with subsequent generations and current day homesigners (child and adult), thus provides a living historical record of an emerging language. Although generations of signers and adult homesigners have been studied in Nicaragua, and child homesigners have been studied in other cultures, no one has studied the same linguistic properties across all of these groups, thus limiting the field´s ability to determine how each of these varying circumstances contributes to the growth of a linguistic property. The proposed research will chart changes in 3 central aspects of sentence structure (verb structure, argument-specification, and sentence-modulation) across these populations and has 5 aims (1) To probe the structures child Nicaraguan homesigners use for these 3 functions, and thus explore the contribution children make to linguistic structure. (2) To probe the structures that adult Nicaraguan homesigners use for the 3 functions, and thus explore the impact that cognitive and social maturity has on emerging linguistic structure. (3) To probe the structures that the first cohort of NSL use for the 3 functions, and thus explore the impact that being a receiver, as well as a producer, of a sign system has on the structure of that system. (4) To probe the structures that subsequent cohorts of NSL use for the 3 functions, and thus explore the role that transmission across generations plays in structuring a linguistic system. (5) To probe how hearing speakers in Nicaragua use gesture, with speech and without it, when describing the same situations; gesture may provide the raw materials out of which the deaf individuals in Studies 1-4 forge their sign systems. The proposed research is designed to identify the capacities that children bring with them to language learning, thereby enabling educators to better help deaf children and hearing children with language disabilities learn a conventional language, be it signed or spoken
Keywords: Adolescent; Adult; Affect; Age; Child; China; Cochlear Implants; Cognitive; cohort; Communication; Communities; design; Development; Disadvantaged; Exhibits; Family; forging; Friends; Generations; Gestures; Goals; Growth; Hearing; Hearing Impaired Persons; hearing impairment; Individual; Language; Language Development; Language Disorders; Learning; Life; Linguistics; Manuals; Meleagris gallopavo; member; Modeling; natural language; Nicaragua; Nicaraguan; Oral; Parents; Partner Communications; peer; Play; Population; prevent; programs; Property; Relative (related person); Research; resilience; Role; Schools; Series; Sign Language; social; Special Education; Specific qualifier value; Speech; Staging; Structure; Students; System; Time; transmission process; Variant; Vocabulary; Work
Relevance: The proposed research is designed to identify the capacities that children bring with them to language learning, thereby enabling educators to better help deaf children and hearing children with language disabilities learn a conventional language, be it signed or spoken
Project start date: 1988-09-01
Project end date: 2016-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-10-067
2R01DC000491-24 (2011): $430285
Sponsored Links Excellgen http://Excellgen.com
INCREASING YOUNG ADULT SMOKERS´ DEMAND FOR INTERNET-BASED CESSATION TREATMENT
J Susan, Professor, Ihrp
University Of Illinois At Chicagocity: Chicago country: United States (us)
Grant 5R01CA134861-03 from National Cancer Institute
Abstract: Cigarette smoking remains the number one cause of premature morbidity and mortality in the United States. National data show reductions in smoking prevalence among all age groups except for 18 to 24 year old young adults. Smoking prevalence in this age group is estimated at 24%, and this rate has held steady since 2003. National data indicate that compared to older adults, young adults are less successful at quitting, and they use treatment less often. Even though a sizeable proportion (72%) of young adult smokers are motivated to quit, and 49% have made a serious attempt to quit in the past year, only 4% of young adult smokers who attempted to quit in 2005 reported using behavioral treatment. Randomized trials of cessation treatments that report outcomes by age group show comparable outcomes for young adult and other adult smokers. Thus, quit rates among young adult smokers could improve with increased reach of evidence-based cessation treatments into this population. The underlying premise of the proposed study is that the development of effective strategies aimed to increase demand for evidence-based smoking cessation treatments among young adult smokers will accelerate rates of cessation in this key target population. The proposed study applies innovative research methods to achieve the following specific aims (1) Implement a multi-phase market test strategy to develop a series of theory-driven internet- based messages to encourage use of behavioral cessation treatments among young adult smokers; (2) Implement a randomized controlled efficacy study to identify a minimum of 4 highly efficacious communications; (3) Implement an interrupted time series (ITS) study to assess the effectiveness and cost effectiveness of the communications under real-world conditions to increase young adult smokers´ participation in evidence-based behavioral interventions. The ITS will provide precise detection of the magnitude and duration of trends in the effectiveness of the messages over time in stimulating demand for cessation treatment among young adult smokers; and (4) Conduct a longitudinal cohort study with a sample of young adult treatment participants in order to (a) Describe patterns and degree of engagement with treatment, and (b) Model factors associated with use of treatment, smoking cessation attempts, and successful smoking cessation. Interim data indicate little chance of reaching Healthy People 2010 goals with regard to smoking prevalence. Thus, tobacco use is likely to remain the number one cause of premature death and disability into the next generation of young adult smokers. Despite the availability of effective smoking cessation treatments, demand for these treatments remains disappointingly low, particularly among young adults. Little research exists on strategies to enhance demand for evidence-based treatment. The proposed research will help to bridge this gap between the availability and use of effective smoking cessation treatments
Keywords: 21+ years old; Abstinence; Adult; adult human (21+); adult youth; advanced age; age group; Age Group Unspecified; Aged 65 and Over; base; Behavior Conditioning Therapy; behavior intervention; Behavior Modification; Behavior or Life Style Modifications; Behavior Therapy; Behavior Treatment; Behavioral; Behavioral Conditioning Therapy; behavioral intervention; Behavioral Modification; Behavioral Sciences; Behavioral Therapy; Behavioral Treatment; cease smoking; Cessation of life; Cessation of smoking; Cessation of Treatment; cigarette smoking; cohort; Cohort Studies; Communication; Communication Research; Concurrent Studies; Conditioning Therapy; cost effectiveness; Data; Death; Detection; Development; disability; Effectiveness; Elderly; Elderly, over 65; elders; evidence base; Evidence based treatment; geriatric; Goals; Health; Healthy People 2010; Human, Adult; improved; innovate; innovation; innovative; insight; Internet; late life; later life; Life Style Modification; Market Research; Marketing; Methodology, Research; Methods; Modeling; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Motivation; next generation; older adult; older person; Outcome; Participant; Pattern; Perception; Phase; Population; premature; Process; programs; Programs (PT); Programs [Publication Type]; randomisation; randomization; Randomized; randomized trial; randomly assigned; Relapse; Reporting; Research; Research Methodology; Research Methods; Sampling; senior citizen; Series; smoke cigarette; Smoker; smoking cessation; smoking prevalence; Target Populations; Testing; theories; Time; Tobacco Cessation; Tobacco Consumption; Tobacco use; Tobacco Use Cessation; Treatment Effectiveness; trend; United States; web; Withholding Treatment; world wide web; WWW; young adult
Relevance: Interim data indicate little chance of reaching Healthy People 2010 goals with regard to smoking prevalence. Thus, tobacco use is likely to remain the number one cause of premature death and disability into the next generation of young adult smokers. Despite the availability of effective smoking cessation treatments, demand for these treatments remains disappointingly low, particularly among young adults. Little research exists on strategies to enhance demand for evidence-based treatment. The proposed research will help to bridge this gap between the availability and use of effective smoking cessation treatments
Project start date: 2009-05-01
Project end date: 2014-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-07-070
5R01CA134861-03 (2011): $551010
REGULATION OF ACTIN DYNAMICS IN AIRWAY SMOOTH MUSCLE
J Susan
Indiana Univ-purdue Univ At Indianapoliscity: Indianapolis country: United States (us)
Grant 5R01HL074099-09 from National Heart, Lung, And Blood Institute
Abstract: Actin polymerization and remodeling of the actin cytoskeleton are critical steps in the process of tension generation in airway smooth muscle (ASM). In ASM, the actin cytoskeletal remodeling process is distinct from the actomyosin crossbridge cycling system, and may uniquely regulate specialized physiological properties of airway smooth muscle such as mechanical adaptation, which is critical for the regulation of airway tone when they are stretched during breathing. The long term goals of this project are to determine the molecular processes that regulate actin cytoskeletal remodeling in ASM, and to describe the mechanisms by which dynamic cytoskeletal events are coupled to contractile activation of the muscle by receptor agonists and external stimuli. Studies are proposed to address the hypothesis that vinculin and cofilin are key effectors in the regulation of cytoskeletal processes that determine the mechanical and contractile properties of airway smooth muscle, and that the activation states of these proteins are regulated by contractile and relaxing stimuli in ASM through the activation of Rho GTPases. Vinculin is proposed to act as a molecular switch for the regulation of connections between cytoskeletal actin filaments and membrane adhesion protein complexes. The formation of such connections may be critical for the regulation of tension transmission from the contractile apparatus to the extracellular matrix in smooth muscle. Cofilin is proposed to function to severe actin filaments and to generate the pool of G (monomeric) actin used for actin remodeling and polymerization. The specific aims of the project are 1) Determine the role of vinculin in regulating connections between actin filaments and membrane adhesion complexes in ASM in response to agonists that regulate airway smooth muscle contractility. 2). Determine the role of cofilin in the remodeling of actin filaments by stimuli that regulate airway contractility, and evaluate the effects of the modulation of the actin remodeling on the static and dynamic mechanical properties of ASM. 3). Evaluate the mechanisms by which small Rho GTPases couple agonist stimulation to the regulation of cytoskeletal dynamics in ASM. These aims will be addressed in a series of experiments that take advantage of novel technology that enables the expression of endogenous and recombinant proteins to be manipulated in intact airway smooth muscle tissues and the effects on their physiologic, cellular and biochemical properties determined. The activation of these key cytoskeletal effector proteins may directly couple critical cytoskeletal processes to agonist stimulation in airway smooth muscle, thus they may constitute novel targets for therapeutic intervention in the treatment of abnormalities in the regulation of airway tone and responsiveness such as asthma. The proposed experiments are directly relevant to public health. These studies will characterize novel fundamental mechanisms by which airway smooth muscle contractility and responsiveness is regulated under the normal conditions of breathing, and determine how physiologic agents that contract airway smooth muscle activate these processes. The studies will determine the function and regulation of key molecules that act to regulate airway smooth muscle responsiveness through theses novel mechanisms. This information is necessary for the design and development of appropriate therapeutic agents to treat asthma and airway hyperreactivity
Keywords: Actins; Actomyosin; Address; Adhesions; Agonist; airway hyperresponsiveness; Asthma; Binding (Molecular Function); Biochemical; Breathing; Cell membrane; Cell model; cell type; Cells; cofilin; Complex; Contracts; Coupled; Cultured Cells; Cytoskeletal Modeling; Cytoskeletal Proteins; Cytoskeleton; design; Development; Environmental air flow; Event; Extracellular Matrix; Family; G-Protein-Coupled Receptors; Generations; Goals; In Vitro; Integrins; macromolecular assembly; Mechanics; member; Membrane; Microfilaments; Modeling; Molecular; Molecular Conformation; Multiprotein Complexes; Muscle; Muscle Cells; Muscle Contraction; Muscle strain; Myosin Light Chains; new technology; new therapeutic target; novel; Phosphorylation; Physiological; Play; polymerization; Process; Property; protein complex; Protein Dephosphorylation; Proteins; public health medicine (field); receptor; Recombinant Proteins; Regulation; Research; research study; respiratory smooth muscle; response; rho GTP-Binding Proteins; Role; Series; Shapes; Signal Pathway; Smooth muscle (tissue); Smooth Muscle Actin Staining Method; Smooth Muscle Myocytes; Stimulus; Stretching; System; Therapeutic Agents; Therapeutic Intervention; transmission process; Vinculin
Project start date: 2003-08-15
Project end date: 2012-04-30
Budget start date: 1-JUL-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01HL074099-09 (2011): $385000
ENVIRONMENTAL & BIOLOGICAL VARIATION AND LANGUAGE GROWTH
J Susan
University Of Chicagocity: Chicago country: United States (us)
Grant 5P01HD040605-09 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Acquiring the ability to communicate using natural language and symbolic gestures is a uniquely human capacity that underlies the exchange of information among people. There is as yet no consensus concerning how susceptible this process is to environmental and biological variation. The proposed Program Project focuses on this issue, exploring the extent and the limits of the language-learning process. To examine language growth in the face of environmental variation (Project I), 60 children, selected to represent the demographic range of the Chicago area, were observed between the ages of 14 and 58 mos. and will continue to be followed as they enter school and learn to read. Assessments will be made of child spontaneous speech, along with narrative and reading skills from 5 to 10 years. Using these data, growth curves will be constructed for each child to track language and reading development across time, and to examine children´s linguistic and reading progress in the later years (5-10 yrs.) in relation to their developmental trajectory during the early years (14-58 mos.). To explore language growth in the face of biological variation (Project III), 40 children with unilateral brain injury who were observed from 14 to 58 mos. will be followed from 5 to 10 years with an eye toward determining whether environmental variation plays the same role in predicting their language and reading growth as it does in children who have not suffered brain injury. Along with traditional measures, two additional probes will be used. (1) Gesture will be examined in children from Projects l-lll to determine whether children who are delayed in speech relative to their peers use gesture to compensate for those delays (Project II). (2) The brain bases underlying linguistic and gestural competence will be assessed in children from Projects l-lll using fMRI techniques (Project IV). Three cores will provide broad support to the projects the Administrative Core A, the Data Collection and Transcription Core B, and the Statistical Core C. The proposed work builds on five years of longitudinal data in a diverse sample, and thus offers a unique opportunity to explore the impact that early language learning has on the oral and written skills that children develop once schooling has begun. The data have the potential to shed light on the factors that contribute to the gap between children from high vs. low socioeconomic groups on the first day of school, and may even point to ways of shrinking that gap
Project start date: 2001-04-01
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5P01HD040605-09 (2011): $1355207