FLEXIBILITY OF LEARNING IN INFANT SKILL ACQUISITION
E Karen, Professor Of Psychology
New York Universitycity: New York country: United States (us)
Grant 4R37HD033486-17 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Keywords: Accidental Injury; Adult; Affect; base; Behavioral; Biomechanics; Child; Code; computerized; Congenital Abnormality; Development; Dimensions; Eating Disorders; Elderly; Eye; falls; flexibility; Goals; Head; infancy; Infant; Injury; Instruction; Learning; Longevity; Monkeys; Motor; Motor Skills; Movement; Obesity; Perception; Pregnancy; Principal Investigator; Procedures; Process; programs; Research; skill acquisition; Source; System; Technology; Visual; young adult
Project start date: 1996-05-24
Project end date: 2016-04-30
Budget start date: 9-MAY-2011
Budget end date: 30-APR-2012
4R37HD033486-17 (2011): $591038
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to E Karen
OUTLOOK-AN INTERVENTION TO IMPROVE QUALITY OF LIFE IN SERIOUS ILLNESS
E Karen
Duke Universitycity: Durham country: United States (us)
Abstract: This study will demonstrate whether an end-of-life preparation and completion intervention reduces anxiety, depression, pain and other symptoms and improves functional status, spiritual well-being, and quality of life. If effective, the intervention offers a brief, inexpensive, and transportable non-physician treatment method for improving the experience of individuals in the latter stages of life-limiting illness. Efforts to improve end-of-care often focus on pain and symptom control, but few, if any, effective interventions exist addressing preparation arid completion. We designed an end-of-life preparation and completion intervention, based on the human development literature identifying life completion as a developmental task and the robust evidence in health communication and clinical psychology that addresses the value of expressing emotions and stress on health outcomes. Our specific aims are 1) evaluate the impact of an intervention that promotes discussions of end-of-life preparation and completion on health outcomes in dying persons, including pain and symptoms, physical-function, emotional function (anxiety and depression), spiritual well-being, and quality of life at the end of life and 2) evaluate the content of the such discussions, examining task variation associated with gender, ethnicity, socio-economic status, quality of communication with family, spirituality, and stage of illness to improve understanding of the need for tailored intervention content based on demographics or location in the trajectory of illness. We propose a randomized control trial to evaluate the intervention. 140 patients with advanced cancer, CHF, or COPD will be randomly assigned into one of two intervention groups and complete a brief battery of pre-test measures. Subjects in the first group ("treatment") will meet with a facilitator three times for a period of forty-five minutes each. In the first session, subjects will be asked to discuss issues related to life review. A week later, participants will be asked to speak in more depth about issues such as regret, forgiveness and things left undone. In the final session, a week hence, subjects will focus on heritage and legacy. The subjects in the second group ("attention control") will meet with a facilitator three times for a period of forty-five minutes each and be asked to listen to a non-guided relaxation CD. One week and two weeks later, participants in all groups will receive post-test measures administered by a blinded interviewer
Keywords: Address; Advanced Malignant Neoplasm; Anxiety; Attention; base; Blinded; Caring; Chronic Obstructive Airway Disease; Clinical; clinical care; Clinical Nursing; Clinical Psychology; Communication; cost; demographics; design; Development; Educational Curriculum; effective intervention; Emotional; end of life; Ethnicity aspects; experience; Expressed Emotion; Family; forgiveness; Fostering; functional status; Gender; group intervention; Health; Health Communication; Human Development; improved; Individual; insight; Intervention; Interviewer; Learning; Left; Life; Literature; Location; Measures; Medical; meetings; Mental Depression; Methods; Nurses; Outcome; Pain; Palliative Care; Participant; Patients; Personal Satisfaction; Persons; Physical Function; Physicians; Preparation; Provider; Publications; Quality of life; Randomized; Randomized Controlled Trials; Regrets; Relaxation; Self Management; Services; Skilled Nursing Facilities; Social work (field); Socioeconomic Status; Spirituality; Staging; Stress; Symptoms; Testing; therapy design; Time; Variant
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5P01NR010948-04_0003 (2011): $72126
GET ACTIVE ORLANDO: WALKING, BICYCLING, GARDENING
E Karen
University Of Central Floridacity: Orlando country: United States (us)
Grant 5R01HL091793-02 from National Heart, Lung, And Blood Institute
Abstract: The purpose of this Community-Based Participatory Research project is to implement, evaluate, and disseminate the immediate and 2-year effects of walking, bicycling, and community gardening approaches to enhancing physically active lifestyles among urban-dwelling older adults and low-income ethnic minorities within a conducive, appealing built environment. A strong emphasis on the importance of physical activity as it impacts current and future health across the lifetime pervades research journals and lay magazines, nationally-based physical activity programs for all ages, health education programs for the public from a variety of sources, and public service announcements. Study results are expected to identify effective strategies and efficient programs to foster physically active lifestyles in sustainable community-based programs that can be readily adopted by other cities across the nation
Keywords: Adopted; Adoption; Adult; Advisory Committees; Age; Area; base; Bicycling; Cardiovascular Diseases; Child; Chronic Disease; Cities; Clinical; Communities; community based participatory research; Databases; design; Diabetes Mellitus; Elderly; Elements; Environment; ethnic minority population; Event; Feedback; Fostering; Foundations; Funding; Future; Government Officials; Health; Health education; Impaired cognition; improved; Individual; Intervention; Investigation; Journals; Life; Life Style; Low income; Maintenance; Malignant Neoplasms; Mental Depression; Minority; Mission; Modality; Mortality Vital Statistics; Obesity; Osteoporosis; Persons; Physical activity; Policies; Population; Program Evaluation; programs; Research; Research Project Grants; Scientist; Secondary Prevention; Seminal; Services; Source; State Government; Taxes; Time; Walking; Wood material; Work
Project start date: 2009-08-17
Project end date: 2012-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2012
PFA/PA: PAR-07-283
5R01HL091793-02 (2010): $632526
PROFILING PATHOLOGICALLY NORMAL APOE VARIANTS TO IDENTIFY PATHWAYS FOR AD
E Karen, Professor
Columbia University Health Sciencescity: New York country: United States (us)
Grant 5R21NS071836-02 from National Institute Of Neurological Disorders And Stroke
Abstract: The project aims to explore why inheritance of the E4 variant of apolipoprotein E (ApoE4) is a significant risk factor for onset and progression of AD. The rationale for this proposal is driven by several observations 1) that inheritance of the ApoE4 variant is a very strong risk factor for AD relative to inheritance of ApoE3, 2) that manifestations of altered brain morphology and function are apparent in ApoE4 individuals, early in life, decades before plaques and tangles are apparent, and 3) that inheritance of ApoE4 is a risk factor for several diseases suggesting a general deficit in pathways affecting neuroprotection, repair, cell survival etc. We anticipate that altered pathways impacted by ApoE of relevance to AD can be identified by a comparison of gene profiles between vulnerable cell populations of ApoE variants. Our second speculation is that while it is clear that ApoE4 affects the accumulation of amyloid-beta (A2) due to its effects on clearance, there are pathways mediated by ApoE receptor family signaling that could also provide a secondary point of vulnerability. This is demonstrated by the observation that inheritance of ApoE4 is a risk factor for other diseases or events that involve brain injury, and that the altered morphology of neurons of ApoE4 individuals suggests less capacity to respond favorably to injury. The combination of a poor overall response to insult, coupled with selective vulnerability of cell types that rely heavily on ApoE mediated pathways could explain why inheritance of ApoE4 variant is more of a problem for AD than other neurodegenerative diseases. The project aims to identify pathways at risk in both humans and a mouse model with different ApoE variants. We anticipate that these studies will generate new ideas about the etiology of AD in this large population group that might suggest novel preventative or therapeutic measures. ApoE4 carriers are at significantly heightened risk of AD but clinical trials are becoming increasingly stratified to exclude ApoE4 carriers. As it is possible to test for ApoE genotype very early in life, it is imperative to identify pathways that increase risk as it may be possible to intervene therapeutically from an early age. RNA profiling vulnerable cell populations from pathologically normal ApoE4 carriers is expected to identify novel pathways at risk, allowing for biomarker and therapeutic developments. Performing identical experiments on ApoE targeted mice will provide corrolatory data, as well as generating novel information on this valuable mouse model of an important AD risk factor
Keywords: abeta accumulation; Affect; Age; age related; aging brain; Algorithms; Alleles; Alzheimer`s disease risk; Antibodies; Apolipoprotein E; apolipoprotein E-3; apolipoprotein E-4; Apoptosis; area striata; biomarker; Brain; Brain Injuries; brain morphology; Brain region; brain tissue; Cell Survival; cell type; Cells; Clinical Trials; Consensus; Coupled; Data; Data Set; Degenerative Disorder; design; Development; Disease; entorhinal cortex; Ethnicity aspects; Etiology; Event; Family; Frequencies (time pattern); Future; Gender; Gene Expression; General Population; Genes; genetic linkage; genetic variant; Genomics; Genotype; Head; hippocampal pyramidal neuron; Human; Image; in vivo; Individual; Inflammation; Inherited; Injury; insight; Lasers; Late Onset Alzheimer Disease; LDL-Receptor Related Protein 1; Life; Link; Measures; Mediating; Metabolism; Microarray Analysis; Microscopy; Modeling; Molecular; Molecular Profiling; Morphologic artifacts; Morphology; mouse model; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; neurogenesis; Neurons; neuroprotection; novel; Pathogenesis; Pathology; Pathway Analysis; Pathway interactions; Patients; Phosphorylation; Population; Population Group; Presenile Alzheimer Dementia; Process; Protein Analysis; Proteomics; public health relevance; receptor; Regulation; Relative (related person); repaired; Reporting; Research Design; research study; Resistance; response; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; RNA; Sampling; Signal Transduction; Testing; Therapeutic; therapeutic development; Transgenic Mice; Variant
Relevance: ApoE4 carriers are at significantly heightened risk of AD but clinical trials are becoming increasingly stratified to exclude ApoE4 carriers. As it is possible to test for ApoE genotype very early in life, it is imperative to identify pathways that increase risk as it may be possible to intervene therapeutically from an early age. RNA profiling vulnerable cell populations from pathologically normal ApoE4 carriers is expected to identify novel pathways at risk, allowing for biomarker and therapeutic developments. Performing identical experiments on ApoE targeted mice will provide corrolatory data, as well as generating novel information on this valuable mouse model of an important AD risk factor
Project start date: 2010-09-30
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-10-069
5R21NS071836-02 (2011): $198042
FLEXIBILITY OF LEARNING IN INFANT SKILL ACQUISITION
E Karen, Professor Of Psychology
New York Universitycity: New York country: United States (us)
Grant 3R37HD033486-15S1 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: The overall goal of this research is to advance the understanding of flexibility in motor skill acquisition - how infants, children, and adults learn to select appropriate movements and modify them as necessary in accordance with the current constraints on action. Flexibility is imperative for adaptive motor decisions because the constraints on action (e.g., environment, bodies/skills, and penalties for error) are continually changing. Empirical work indicates that everyday experience with balance and locomotion provides infants the wherewithal to flexibly adapt motor decisions to novel changes in their bodies, skills, and environment. Learning, however, is specific to each perception-action system in postural development (sitting, crawling, and walking). Specific Aim #1 is to test the flexibility and specificity of infants´ motor decisions. The proposed experiments use an age-matched design to test flexibility within experienced perception-action systems under conditions of altered body dimensions/skills and penalties for error and to test specificity between experienced vs. newly acquired perception-action systems. Specific Aim #2 is to describe the time course of flexibility. The proposed studies use a microgenetic design to test experience-related changes in infants´ ability to cope with novel constraints on action and a cross-sectional design to test age-related changes in flexibility from infancy to old age. Specific Aim #3 is to assess flexibility in "specialized" perception-action systems - skills acquired after infancy by only a subset of children due to specific opportunities and demands. Proposed studies use a "monkey bar" paradigm to test children´s motor decisions under conditions of altered body constraints and penalties for error. Across all experiments, a psychophysical method will be used to quantify the correspondence between motor decisions and actual possibilities for action. As the penalties for errors in the proposed studies are falling or entrapment, findings will provide insight into these two leading causes of accidental injury. Falling from monkey bars is the leading cause of playground injury in middle childhood. In addition, the proposed methods, conceptual framework, and findings can provide the basis for assessing flexibility in children with motor impairments and for tracking improvements in flexibility with therapy
Keywords: Accidental Injury; Accounting; Adult; Age; age related; base; Behavior; Child; Childhood; coping; coping mechanism; Cues; design; Development; Dimensions; Environment; Equilibrium; experience; falls; flexibility; Funding; Goals; Health; infancy; Infant; Injury; insight; Intervention; Knowledge; Learning; Locomotion; Longevity; Maintenance; Methods; Monkeys; Motor; motor impairment; Motor Skills; Movement; novel; Perception; Procedures; programs; Psychological Transfer; Psychophysiology; Regimen; Research; Research Personnel; research study; response; Safety; Series; skill acquisition; skills; Solutions; Specificity; System; Testing; Time; Walking; Work
Project start date: 2010-02-03
Project end date: 2011-01-31
Budget start date: 3-FEB-2010
Budget end date: 31-JAN-2011
3R37HD033486-15S1 (2010): $74613
5R37HD033486-16 (2010): $400012
NC GENES: NORTH CAROLINA CLINICAL GENOMIC EVALUATION BY NEXTGEN EXOME SEQUENCING
E Karen
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Grant 1U01HG006487-01 from National Human Genome Research Institute
Abstract: Technological developments in the field of genomics now afford the opportunity to define the complete sequence of an individual´s genome in a rapid and affordable manner. Such "whole genome sequencing" and its simpler corollary, "whole exome sequencing" (WES), have already established themselves as powerful research tools. The natural next step in the evolution of this technology is its direct application in the clinical arena. However, while such technology holds considerable clinical promise, tremendous challenges exist in applying it and deriving practical benefit to patients. In this proposal we outline a highly interdisciplinary approach to identifying, confronting and overcoming the major challenges which must be met in order to implement deep sequencing technology in clinical medicine. Aim 1 will explore the use of WES as a diagnostic tool in the care of a broad array of patients, evaluate its performance, identify critical clinical characteristics which can guide its application and measure the impact of such information on patients and providers. Aim 2 will tackle one of the most pressing challenges in the clinical application of WES the inevitable generation of "collateral" or "bystander" information. Educational materials will be developed to enable patients to make decisions about appropriate return of results and the impact of collateral information will be assessed at the level of the provider, laboratory and patient. The third major challenge in clinical implementation of genomic medicine, how do deal with vast amounts of information, will be addressed by Aim 3. A clinically oriented "binning" structure will be created and refined for classifying, storing and transmitting data within practical categories so as to make sense of the large amounts of data generated. Finally, as we stand on the cusp of genomic medicine, we must ensure that all have access to its benefits. Thus, Aim 4 will pursue clinical WES in traditionally underrepresented populations to identify special opportunities and challenges in the clinical translation of this new tool to the broadest possible population. Our ultimate aim is to establish a set of best practices to guide future implementation of robust genomic technologies for the real and practical betterment of human health. Genomic medicine has tremendous potential to improve human health by facilitating improved diagnosis, offering deep insight into mechanisms of disease and by enabling individually targeted prevention and treatment. In this proposal we will confront the major challenges which stand between genomic medicine and its broad implementation to a diverse population
Keywords: Address; base; Caring; Categories; Characteristics; Clinical; clinical application; Clinical Medicine; Communities; Consensus; Data; Decision Making; Development; Diagnosis; Diagnostic; direct application; Disease; Educational Materials; Ensure; Ethics; Evaluation; Evolution; exome; Fostering; Frequencies (time pattern); Future; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genome; genome sequencing; Genomics; Goals; Health; Human; improved; Incidental Findings; Individual; insight; interdisciplinary approach; Laboratories; Learning; Lesion; Measures; medically underserved population; Medicine; meetings; Minority; Modeling; next generation; North Carolina; novel strategies; Patient Care; patient population; Patients; Pattern; Performance; Plant Roots; Population; Population Heterogeneity; Prevention; Provider; Reporting; Research; shared decision making; Signs and Symptoms; Structure; Surveys; Technology; Time; tool; Translations; Work
Relevance: Genomic medicine has tremendous potential to improve human health by facilitating improved diagnosis, offering deep insight into mechanisms of disease and by enabling individually targeted prevention and treatment. In this proposal we will confront the major challenges which stand between genomic medicine and its broad implementation to a diverse population
Project start date: 2011-12-05
Project end date: 2015-11-30
Budget start date: 5-DEC-2011
Budget end date: 30-NOV-2012
1U01HG006487-01 (2012): $407704
CXCR4 CHEMOKINE RECEPTOR REGULATION OF ERK MAP KINASE
E Karen, Associate Professor
Mayo Cliniccity: Rochester country: United States (us)
Grant 5R01GM059763-11 from National Institute Of General Medical Sciences
Abstract: T lymphocyte activation and migration are critical for normal immune functions. Signaling by both the T lymphocyte antigen receptor-CD3 complex (TCR) and chemokine receptors such as CXCR4 are extensively cross-regulated, however, until recently little was known about the molecular mechanisms responsible for this cross-regulation. Moreover, although CXCR4 is ubiquitously-expressed, highly conserved, and essential for Human Immunodeficiency Virus-1 (HIV-1) infection of T cells, few specific immune function(s) of T lymphocyte CXCR4 have been proposed. The CXCR4 ligand, SDF-1, is constitutively expressed at specific anatomic sites, include the bone marrow, lymph nodes, and gut. SDF-1/CXCR4 signaling on T cells may, therefore, critically modulate T cell immune activation in these locations. Our results during the last cycle of this grant (recently published in Immunity) indicate that SDF-1 stimulation of CXCR4 produces signals in T cells via a novel mechanism by inducing the formation of CXCR4/TCR complexes which then utilize the TCR ITAM domains and TCR-associated signaling molecules to activate the Ras/ERK MAP kinase pathway. Our preliminary results further indicate that this pathway mobilizes AP-1-dependent transcription factors that are responsible for SDF-1 co-stimulation of IL-10 production and secretion by T cells. Experiments proposed below are designed to further characterize three key areas of this novel signaling pathway. Aims 1 & 2 will test the central hypothesis that SDF-1 stimulates .the formation of CXCR4/TCR complexes by enhancing the trafficking of CXCR4 into late recycling endosomes that also contain constitutively-recycling TCR molecules, and that the clumping of these vesicles near the MTOC and Golgi permits CXCR4/TCR complexes to signal via Ras-ERK pathway components on the endosomes and/or Golgi. Aim 3 will test the related hypothesis that this signaling pathway enhances T cell secretion of IL-10 and thereby critically modulates immunity. Together, the results of the proposed studies will characterize key points of the recently-discovered novel mechanism by which CXCR4 signals in T cells, and that may also participate in CXCR4-mediated migration, integrin regulation and HIV-1 pathobiology. In addition, the results of the proposed studies will delineate the importance of this pathway for CXCR4 co-stimulation of T cell IL-10 secretion and immune regulation, results that have the potential improve therapies of human autoimmune diseases that depend on IL-10
Keywords: Activator Protein-1; Address; Ag Recognition Activation Motif; AIDS Virus; Anatomic Sites; Antigen Receptors; Antigens, LD; AP-1; AP-1 Enhancer-Binding Protein; AP1; AP1 protein; ARAM; Area; Autoimmune Diseases; autoimmune disorder; autoimmune inflammatory bowel disease; Autoimmune Status; Autoimmunity; Biochemical; Biological Function; Biological Process; biological signal transduction; Blast Transformation; Blastogenesis; body movement; Body Tissues; Bone Marrow; CD3; CD3 Antigens; CD3 Complex; CD3 molecule; Cell Communication and Signaling; Cell Locomotion; Cell Migration; cell motility; Cell Movement; Cell secretion; Cell Signaling; Cell Surface Receptors; cell type; Cellular Migration; Cellular Secretion; Chemokine (C-X-C Motif) Ligand 12; chemokine receptor; Complex; Coupling; CSIF; CSIF-10; CXC-R4; CXCL12 protein; CXCR-4; CXCR4; CXCR4 gene; cytokine; Cytokine formation-inhibiting factor (mouse clone F115 protein moiety reduced); Cytokine Synthesis Inhibitory Factor; D2S201E; Data; design; designing; Elements; Endocytosis; Endosomes; Enhancer-Binding Protein AP1; ERK MAP Kinases; experiment; experimental research; experimental study; Extracellular Matrix, Integrins; Extracellular Signal Regulated Kinases; extracellular signal related kinase; Extracellular Signal-Regulated MAP Kinases; FB22; Golgi; Golgi Apparatus; Golgi Complex; Grant; hIRH; HIV-1; HIV-I; HIV1; HM89; HSY3RR; Human; Human immunodeficiency virus 1; human T cell leukemia virus III; human T lymphotropic virus III; Human, General; IL-10; IL10; IL10A; Immune; immune activation; immune function; Immune Function, Cellular; Immunity; Immunodeficiency Virus Type 1, Human; Immunoreceptor Tyr-Based Activation Motif; Immunoreceptor Tyrosine-Based Activation Motif; improved; Infection; Integrins; Interleukin 10 Precursor; Interleukin-10; Intracellular Communication and Signaling; Intracellular Membranes; Investigators; ITAM; LAP3; LCR1; LESTR; Ligands; Location; lymph gland; Lymph node proper; lymph nodes; Lymphoblast Transformation; Lymphocyte Activation; Lymphocyte antigen; lymphocyte differentiation antigen; Lymphocyte Stimulation; Lymphocyte Transformation; Man (Taxonomy); Man, Modern; Mediating; Membrane; membrane structure; Microtubule-Organizing Center; migration; Molecular; Motility; Motility, Cellular; mouse model; Movement; MTOC; novel; NPY3R; NPYR; NPYRL; NPYY3R; OKT3 antigen; pathway; Pathway interactions; Pre-B Cell Growth Stimulating Factor; Production; programs; Programs (PT); Programs [Publication Type]; Publishing; receptor; Receptor Protein; Receptosomes; Recycling; Regulation; Research Personnel; research study; Researchers; response; Reticuloendothelial System, Bone Marrow; Reticuloendothelial System, Lymph Node; SDF-1; SDF-1alpha; Sdf1 protein; self recognition (immune); Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Molecule; Solid; Stromal Cell-Derived Factor 1; stromal cell-derived factor-1alpha; T-Cells; T-Lymphocyte; T3 Antigens; T3 Complex; T3 molecule; Testing; Threonine/Tyrosine Protein Kinase; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; Tissues; trafficking; transcription factor; Transcription Factor AP-1; VESCL; Vesicle
Project start date: 1999-09-30
Project end date: 2011-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
5R01GM059763-11 (2010): $290110
ENDOCRINE DISRUPTORS: AR REGULATION AND PROSTATE CANCER
E Karen, Associate Professor
Thomas Jefferson Universitycity: Philadelphia country: United States (us)
Grant 5R01ES016675-11 from National Institute Of Environmental Health Sciences
Abstract: Prostate cancer is the most frequently diagnosed cancer and second leading cause of cancer death in the United States. Androgen receptor (AR) activity is required for prostate cancer growth, and therapeutic regimens for prostatic adenocarcinoma (CaP) are directed toward ablation of AR activity. Despite the initial efficacy of these therapies, recurrent tumors ultimately arise wherein AR has been inappropriately re-activated. No effective treatment exists for recurrent tumors, which lead to patient death. As such, there is an urgent need to identify the comprehensive set of factors that contribute to AR re-activation and tumor recurrence. We have shown that selected endocrine disrupting compounds (EDCs) prevalent in the environment can impinge on the most common mutant of AR that arises during tumor progression (AR-T877A) to stimulate receptor activity and concomitant cellular proliferation. Our new data demonstrate that this action of EDCs has clinical consequence, wherein a known EDC (bisphenol) increased tumor growth and shortened the time to tumor recurrence. Moreover, we showed that several tumor-derived AR mutants gain sensitivity to selected EDCs. Thus, these findings strongly support the central hypothesis of the present proposal, wherein secondary mutations known to occur during tumor progression can sensitize cells to EDC activity, and through these mechanisms EDCs can significantly impact the response to prostate cancer therapy. Here, we delineated 3 specific aims which challenge this hypothesis by first discerning the molecular mechanisms by which EDCs impinge on mutant AR function (Aim 1), identifying the comprehensive cohort of secondary alterations that sensitize cells to EDC activity (Aim 2), and challenging the biological consequence of EDC exposure in the presence of these secondary alterations using new models of disease (Aim 3). Combined, it is our belief that this proposal rigorously addresses the molecular and biological significance of EDC exposure on prostate cancer management and outcome. Given the persistence of each studied EDC in the American population, these studies may have significant impact on understanding the factors that impinge upon prostate cancer growth
Keywords: Ablation; Address; American; Androgen Receptor; Androgens; Belief; Biological; bisphenol A; Bypass; cancer cell; Cancer Cell Growth; cancer diagnosis; Cancer Etiology; cancer therapy; Cell Cycle Progression; Cell Proliferation; Cells; Cessation of life; chromatin modification; Clinical; cohort; Competence; Cytotoxic Chemotherapy; Data; Disease; Disease model; Disease remission; effective therapy; Employee Strikes; Endocrine Disruptors; enhancing factor; Environment; environmental agent; Environmental Pollution; Event; Frequencies (time pattern); Funding; gain of function; Gene Expression Profile; Gene Targeting; Goals; Growth; Growth Factor; in vivo; Indolent; Intervention; Investigation; Lead; Ligands; Malignant neoplasm of prostate; Mediating; men; Modality; Modeling; Molecular; Morbidity - disease rate; mutant; Mutation; Nature; Nuclear Receptors; Outcome; overexpression; Patients; Population Study; Prevention; Prostate Adenocarcinoma; Prostate Cancer therapy; Prostatectomy; Prostatic Neoplasms; Publishing; Radiation therapy; receptor; Receptor Activation; receptor function; Receptor Signaling; Recurrence; Recurrent disease; Recurrent tumor; Regimen; Regulation; Resistance; response; Second Primary Cancers; Signal Transduction; Specificity; Therapeutic; Therapeutic Intervention; Time; transcription factor; Treatment Efficacy; tumor; tumor growth; tumor progression; Tumor-Derived; United States; Xenograft Model
Project start date: 2002-04-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5R01ES016675-11 (2011): $362089
CYCLIN D1: REPERCUSSIONS OF AR CONTROL AND ALTERNATIVE SPLICING IN PROSTATE CANCE
E Karen, Associate Professor
Thomas Jefferson Universitycity: Philadelphia country: United States (us)
Grant 5R01CA099996-09 from National Cancer Institute
Abstract: Prostate cancer (PCa) cells are dependent on androgen receptor (AR) function for growth and survival; this dependence is exploited in treatment of disseminated cancers, wherein ablation of AR activity is the first line of therapeutic intervention. While initially effective, recurrent tumors ultimately arise as a result of inappropriately restored AR function. AR is a master regulator of G1-S phase transitions in PCa, and interrogation of this mechanism led to the discovery of significant cross-talk mechanisms between the AR and cell cycle pathways. Cyclin D1 is a major effector of androgen action, and serves specialized functions in PCa that were delineated during the first funding period. Active AR induces cyclin D1 accumulation, thereby stimulating cyclin dependent kinase 4 (CDK4) activity and G1 progression. However, we and others showed that accumulated cyclin D1 binds and inhibits AR activity, thereby engaging a negative feedback loop to attenuate subsequent mitogenic response in AR-positive PCa cells. These actions of cyclin D1 contribute to the observed cell cycle dependence of AR activity in PCa, wherein AR activity is inversely correlated with cyclin D1 expression. Thus, cyclin D1 serves as a "rheostat" that controls the strength and duration of the androgen response. The achieved goals of the first funding period were to dissect the mechanism and regulation of this cross-talk pathway in PCa. Our published and unpublished data demonstrate that cyclin D1 is a major effector of AR activity, and acts through defined mechanisms to alter both AR activity and androgen-dependent proliferation in PCa. Moreover, we demonstrated that aberrations in this process facilitate unleashed AR activity. Thus, this renewal application is based on the hypothesis that abrogation of cyclin D1 transcriptional regulatory function promotes unchecked AR activity in PCa cells, and provides a mechanism to promote tumor development and/or progression. The present renewal application will directly challenge this concept by dissecting the molecular impact of cyclin D1 action (and aberrations thereof) under conditions associated with tumor progression (aim 1), defining the consequence of cyclin D1b, a splice variant of cyclin D1 that is deficient in AR control and is induced in PCa, on androgen mediated gene regulation (aim 2), and determining the oncogenic capacity of cyclin D1b in the prostate (aim 3). Fatal prostate cancer arises as a result of inappropriate androgen receptor (AR) activity, a protein that controls the action of testosterone. We discovered that aberrations in a second gene product (cyclin D1) serve to promote unchecked AR activity and tumor growth. Here, we will determine molecular mechanisms through which cyclin D1 controls AR and determine the importance of this protein in prostate cancer, with the long term goal of devising new therapies to treat this deadly disease
Keywords: Ablation; Alternative Splicing; Androgen Receptor; Androgens; Apoptosis; Attenuated; base; Binding (Molecular Function); Biological Assay; cancer cell; Cell Cycle; Cell Cycle Arrest; Cells; Chromatin; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclins; Cytoplasm; Data; Dependence; Development; Disease; Employee Strikes; Environment; Feedback; Funding; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Targeting; Goals; Growth; Growth and Development function; Health; Histones; Human; In Vitro; in vivo; Lesion; Ligands; Malignant neoplasm of prostate; Malignant Neoplasms; Mediating; Modeling; Molecular; novel; Oncogenic; Pathway interactions; Phase Transition; Premalignant; Process; Prostate; Protein Isoforms; Proteins; Publishing; Receptor Cell; receptor function; Recurrence; Recurrent disease; Recurrent tumor; Regulation; Relative (related person); Repression; response; RNA Splicing; Role; S Phase; Specificity; Testosterone; Therapeutic Intervention; Tissue Recombination; transcription factor; Transcription Repressor/Corepressor; Transcriptional Regulation; Transgenic Model; tumor; tumor growth; tumor progression; Variant; Xenograft Model
Project start date: 2003-06-01
Project end date: 2014-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01CA099996-09 (2011): $241566
TREATMENT OF VITAMIN D INSUFFICIENCY
E Karen, Assistant Professor
University Of Wisconsin Madisoncity: Madison country: United States (us)
Grant 5R01AG028739-03 from National Institute On Aging
Abstract: Osteoporosis is a major health problem in postmenopausal women. At age 50, half of women will suffer an osteoporotic fracture in their remaining lifetime [1], causing increased disability and mortality [1, 2]. Vitamin D deficiency, defined as a serum 25(OH)D <15 ng/mL, contributes to osteoporosis via decreased calcium absorption (CaAb), secondary hyperparathyroidism (HPT), increased bone resorption and decreased bone mineral density (BMD) [3]. Thus, experts agree that patients with vitamin D deficiency should receive vitamin D therapy [4-7]. Vitamin D insufficiency (VDI) is a milder form of hypovitaminosis D defined as a 25(OH)D level between 15 and 30 ng/mL regardless of parathyroid hormone (PTH) status [8]. Experts disagree on whether to treat VDI, as the clinical benefits of therapy are uncertain. Some experts [8-11] insist the optimal 25(OH)D level is e30 ng/mL. By contrast, both the Food and Nutrition Board [12] and NIH Evidence Report No. 158 [13] state that insufficient evidence exists to declare the optimal serum 25(OH)D for bone health, despite review of ~170 studies. Consequently, the Food and Nutrition Board cannot determine a recommended daily allowance for vitamin D. Confusion over the optimal 25(OH)D level results, in part, because previous trials failed to recruit subjects based on initial 25(OH)D levels and/or failed to target or achieve 25(OH)D levels e30 ng/mL. Moreover, secondary HPT, the proposed mechanism by which VDI causes bone loss, occurs in only 10% to 33% of people with VDI [14-17]. As such, people with VDI and normal PTH might not experience clinical benefits from vitamin D therapy. VDI is widespread [15, 18, 19], affecting 26% to 39% of postmenopausal American women with [20] and without [21] osteoporosis. Therefore, determining the ideal 25(OH)D level for optimal calcium homeostasis and bone health is of utmost clinical and public health importance. Our overall goal, congruent with Healthy People 2010 objective 2-9, is to evaluate the effect of vitamin D therapy on the risk of osteoporosis in postmenopausal women with VDI, as reflected by changes in CaAb, BMD and muscle fitness. Our second goal is to evaluate whether a high-dose vitamin D regimen, chosen to achieve and maintain a 25(OH)D level e30 ng/mL [17], is superior in its effects on study outcomes compared to a low-dose vitamin D regimen that can permit continued VDI [22-25]. One in two women past menopause has mildly low vitamin D levels. We don´t know if vitamin D therapy helps these women to have stronger bones that break less easily. We also don´t know whether high-dose vitamin D therapy is better than low-dose vitamin D, in its effects on calcium absorption, bone calcium levels and muscle function. We will ask 250 women past menopause with mildly low vitamin D levels to take part in a one year study. One third of women will receive placebo, one-third will receive low-dose vitamin D and one-third will receive a high-dose vitamin D tablet that keeps their blood levels above 30 ng/mL. We will compare the changes in calcium CaAb, bone calcium levels and muscle fitness among women receiving placebo, low-dose vitamin D and high- dose vitamin D. This study will help decide whether vitamin D therapy lessens the risk of osteoporosis in postmenopausal women, and at what vitamin D dose those benefits occur
Keywords: Acids; Activities of Daily Living; Affect; Affinity; Age; American; Aromatase Inhibitors; authority; base; Blood; bone; Bone Density; bone health; bone loss; Bone Resorption; bone turnover; Calcium; calcium absorption; Caring; Characteristics; Cholecalciferol; Clinical; clinical practice; Clinical Research; Communities; Community Healthcare; Confusion; Data; Densitometry; disability; Disease; Dose; double-blind placebo controlled trial; Elderly; Epidemiologic Studies; Epidemiology; Evaluation; experience; fitness; Food; Fracture; functional outcomes; functional status; Future; Genes; Goals; Health; Health Personnel; Healthy People 2010; Hip Fractures; Homeostasis; Hormones; insight; Intestines; Investigation; Isotopes; Knowledge; Laboratories; malignant breast neoplasm; Measurement; Measures; Mediating; Menopause; Mortality Vital Statistics; Muscle; muscle form; Muscle function; nutrition; older men; older women; Oral; Osteomalacia; Osteoporosis; osteoporosis with pathological fracture; Outcome; Outcome Study; Parathyroid gland; Patients; Pharmaceutical Preparations; Placebos; Plasma; Postmenopause; Production; Proton Pump Inhibitors; public health medicine (field); public health relevance; Publishing; Questionnaires; Randomized; receptor; receptor binding; Recommended Daily Allowances; Recruitment Activity; Regimen; Reporting; Research Design; research study; response; Risk; Role; Secondary Hyperparathyroidism; Serum; Tablets; Testing; time use; United States National Institutes of Health; Vitamin D; Vitamin D Deficiency; Vitamin D3 Receptor; Vitamin Deficiency; Woman; young adult
Relevance: 7. Relevance of proposal, Treatment of Vitamin D Insufficiency One in two women past menopause has mildly low vitamin D levels. We don´t know if vitamin D therapy helps these women to have stronger bones that break less easily. We also don´t know whether high-dose vitamin D therapy is better than low-dose vitamin D, in its effects on calcium absorption, bone calcium levels and muscle function. We will ask 250 women past menopause with mildly low vitamin D levels to take part in a one year study. One third of women will receive placebo, one-third will receive low-dose vitamin D and one-third will receive a high-dose vitamin D tablet that keeps their blood levels above 30 ng/mL. We will compare the changes in calcium absorption, bone calcium levels and muscle fitness among women receiving placebo, low-dose vitamin D and high- dose vitamin D. This study will help decide whether vitamin D therapy lessens the risk of osteoporosis in postmenopausal women, and at what vitamin D dose those benefits occur
Project start date: 2009-09-15
Project end date: 2014-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-07-070
5R01AG028739-03 (2011): $504200
Sponsored Links Excellgen http://Excellgen.com
3R01AG028739-03S1 (2011): $127738
PATHOLOGICAL AND FUNCTIONAL IMPACT OF TAUOPATHY IN VIVO
E Karen, Professor
New York State Psychiatric Institutecity: New York country: United States (us)
Grant 5P01NS048447-06 from National Institute Of Neurological Disorders And Stroke
Abstract: Neurofibrillary pathology is a common feature of a large number of neurodegenerative diseases, the most common of which is Alzheimer´s disease (AD). Although several proteins are disrupted in the pathogenic pathway leading to tangle formation, the microtubule binding protein tau is of significant interest as it is a major component of tangles in the AD brain, and mutations in tau can cause neurodegenerative diseases such as frontal temporal lobe dementia. Understanding how tau becomes pathogenic, and how pathogenic tau disrupts the normal functioning of the neuron ultimately leading to its death are the overall goals of this program. To address these questions, we have taken a multidisciplinary approach. Project 1 will examine gene profiles in single neurons with and without neurofibrillary pathology at different stages to identify what pathways are affected during the disease process. Project 2 will look at the turnover and transport of tau. Project 3 will look at the effect of tauopathy on neuronal integrity using in vivo imaging and project 4 will further put these observations into functional context by examining how pathogenic tau formation impacts system integrity. Project 5 will examine the contribution of phosphorylation or aggregation to the pathogenic process, and will test therapeutic agents that target these systems, as well as explore the role of Abeta in tangle formation, and the use of an Abeta targeting agent to reduce both the amyloid and tangle pathologies of AD. The program will mainly use a new mouse model, the hTau line, that has progressive tauopathy of great relevance to AD. The distribution of this model to program participants will be facilitated by the use of a mouse husbandy core, and coordination of effort and feedback from advisory groups will be facilitated by the use of an administrative core. The individual projects and collective expertise of the program participants will synergize to generate a well-controlled wealth of information about how, and why pathogenic tau forms, and the functional impact of tauopathy at different stages of disease progression. This information, coupled with the judicious use of relevant proof-of concept therapeutic candidates will also begin to address issues of how best to start treating tauopathies such as AD
Keywords: a beta peptide; abeta; abnormal tau; Address; Affect; Alzheimer; Alzheimer beta-Protein; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s amyloid; Alzheimer`s Disease; Alzheimers Dementia; Alzheimers disease; Amentia; Amyloid; Amyloid Alzeheimer`s Dementia Amyloid Protein; amyloid beta; Amyloid Beta-Peptide; Amyloid beta-Protein; Amyloid beta-Protein, Alzheimer`s; Amyloid Fibril Protein (Alzheimer`s); Amyloid Protein A4; Amyloid Substance; amyloid-b protein; beta amyloid fibril; Binding Proteins; Brain; Cessation of life; Coupled; Death; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dementia; dementia of the Alzheimer type; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Disease; Disease Progression; disease/disorder; Disorder; Encephalon; Encephalons; Feedback; gene product; Genes; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Goals; Image; imaging; in vivo; Individual; interdisciplinary approach; interest; Ligand Binding Protein; Mammals, Mice; Mice; Micro-tubule; microtubule associated protein tau; microtubule associated protein tau mutation; microtubule bound tau; microtubule-associated protein tau; microtubule-associated protein tau mutation; microtubule-bound tau; Microtubules; Modeling; mouse model; MT-bound tau; Murine; Mus; mutant tau; Mutation; mutation in microtubule associated protein tau; mutation in microtubule-associated protein tau; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; Neurodegenerative Diseases; Neurodegenerative Disorders; neurodegenerative illness; neurofibrillary degeneration; neurofibrillary lesion; neurofibrillary pathology; neurofibrillary tangle formation; Neurofibrillary Tangles; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; neuronal; Neurons; Participant; pathogenic tau; pathogenic tau gene mutation; pathological change in tau; Pathology; pathway; Pathway interactions; Phosphorylation; primary degenerative dementia; Primary Senile Degenerative Dementia; Process; programs; Programs (PT); Programs [Publication Type]; Protein Phosphorylation; Proteins; Role; senile dementia of the Alzheimer type; social role; soluble amyloid precursor protein; Staging; System; System, LOINC Axis 4; tangle; tangle formation; tau; tau abnormality; tau associated neurodegeneration; tau associated neurodegenerative process; tau factor; tau induced neurodegeneration; tau intronic mutation; tau mediated neurodegeneration; tau mutation; tau neurodegenerative disease; tau neuropathology; tau pathological change; tau Proteins; tauopathic neurodegenerative disorder; Tauopathies; tauopathy; temporal cortex; Temporal Lobe; temporal lobe/cortex; Testing; Therapeutic; Therapeutic Agents
Project start date: 2005-07-01
Project end date: 2011-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2011
5P01NS048447-06 (2009): $1261477
AUTOPHAGIC CLEARANCE OF ABERRANT TAU: BIOCHEMICAL AND THERAPEUTIC IMPLICATIONS
E Karen, Professor
Columbia University Health Sciencescity: New York country: United States (us)
Grant 1R01NS074593-01A1 from National Institute Of Neurological Disorders And Stroke
Abstract: Intracellular inclusions of misfolded proteins are the hallmark of many neurodegenerative diseases. Dysfunction of either of the two proteolytic pathways involved in clearing abnormal or obsolete cellular proteins, the ubiquitin-proteasome system (UPS) and the autophagic-lysosomal system (A-LS) may underlie the development of the disease. Macroautophagy (autophagy), a major degradative pathway of the lysosomal system, plays a significant role in the removal of organelles and protein aggregates that are too large, or that cannot be unfolded by chaperone proteins and that are consequently unable to be degraded by the UPS. An equilibrium exists between autophagosome formation and clearance by lysosomes, and uncompromised vesicular trafficking, heterotypic organelle fusion and lysosomal function are critical for the terminal stages of autophagosomal degradation. The A-LS has been shown to play an important role in the clearance of misfolded, aggregate-prone proteins such as ?-synuclein and huntingtin. In general, we hypothesize that the UPS is upregulated to clear misfolded tau species early during the disease, but the system becomes overwhelmed as larger aggregates of tau accumulate. We envisage that the A-LS is then upregulated in an effort to compensate for the lost UPS activity and to clear the aggregates but ultimately both systems fail resulting in accelerated pathology and decline. The relationship between the accumulation of tau, the interplay between the UPS and A-LS, and the effect of relevant pharmacologic manipulations on outcome measures of relevance to human tauopathy will be assessed in three specific aims. Aim 1 will examine the interplay between the UPS, AL-S and tau accumulation in human tissue from patients with 4R tauopathies and will compare to two mouse models of 4R tauopathy that have been modified to express an autophagic marker. The mouse models will allow us to manipulate components of the autophagic pathways to further study the interplay with the UPS, with specific examination of what happens to specific ubiquitinated forms of proteins to confirm the significance of autophagic sufficiency in tauopathy progression in vivo. Aim 2 will use primary neurons from the aforementioned animal models to test the impact of dysfunction in a particular pathway (abnormal transport of autophagic vacuoles leading to failure of autophagic flux) and its impact on tauopathy, and whether compounds that activate A-LS or reduce the levels of hyperphosphorylated tau ameliorate the pathological phenotype. Aim 3 will identify if compounds identified by NCGC/NIH (National Chemical and Genetic Center) using the MLPCN (Molecular Library Probes Center Network) to reduce huntingtin aggregates and cell death are viable autophagic enhancers that can be used to treat tauopathy. Cumulatively, these studies will add insight into the relationship between clearance pathways, how and when they fail, and the impact of drugs that target autophagy as a therapeutic intervention for the tauopathies Several neurodegenerative diseases known collectively as the tauopathies include, as part of the pathology, intracellular inclusions known as neurofibrillary tangles. Although we do not know how tangles form, or exactly what type of tau (misfolded, hyperphosphorylated, oligomeric or aggregated tau) causes the cell to become dysfunctional, but it is likely that clearing abnormal, misfolded tau proteins will attenuate disease progression and possibly cure, or stabilize the disease. Studies proposed aim to understand better how pathological tau is removed from the cell through either of the two clearance pathways - the ubiquitin-proteasome clearance pathway, or the autophagic clearance pathway. Using mouse models of tauopathy, we will examine how and when these systems fail; their relationship to each other, the consequence of abnormal cellular transport function; and whether novel drug candidates that enhance autophagic clearance are efficacious in a mouse model of tauopathy
Keywords: Address; Animal Model; Attenuated; Autophagocytosis; Autophagosome; Axon; Axonal Transport; Biochemical; Cell Death; Cell model; Cells; chemical genetics; Degradation Pathway; Development; Disease; Disease Progression; drug candidate; Drug Delivery Systems; end stage disease; Enhancers; Equilibrium; Event; Excision; Failure (biologic function); Functional disorder; Genetic; Human; human Huntingtin protein; human tissue; hyperphosphorylated tau; In Vitro; in vivo; insight; Label; Libraries; Lysosomes; Microfluidics; Molecular Bank; Molecular Chaperones; mouse model; multicatalytic endopeptidase complex; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; novel; Organelles; Outcome Measure; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; protein aggregate; protein misfolding; Proteins; Quality Control; Reporter; Role; Staging; synuclein; System; tau aggregation; tau mutation; tau Proteins; Tauopathies; Testing; Therapeutic; Therapeutic Intervention; Tissues; trafficking; Transgenes; Ubiquitin; United States National Institutes of Health; Vacuole; Vesicle
Relevance: Several neurodegenerative diseases known collectively as the tauopathies include, as part of the pathology, intracellular inclusions known as neurofibrillary tangles. Although we do not know how tangles form, or exactly what type of tau (misfolded, hyperphosphorylated, oligomeric or aggregated tau) causes the cell to become dysfunctional, but it is likely that clearing abnormal, misfolded tau proteins will attenuate disease progression and possibly cure, or stabilize the disease. Studies proposed aim to understand better how pathological tau is removed from the cell through either of the two clearance pathways - the ubiquitin-proteasome clearance pathway, or the autophagic clearance pathway. Using mouse models of tauopathy, we will examine how and when these systems fail; their relationship to each other, the consequence of abnormal cellular transport function; and whether novel drug candidates that enhance autophagic clearance are efficacious in a mouse model of tauopathy
Project start date: 2011-07-01
Project end date: 2016-04-30
Budget start date: 1-JUL-2011
Budget end date: 30-APR-2012
PFA/PA: PA-10-067
1R01NS074593-01A1 (2011): $421123
SPATIO TEMPORAL RELATIONSHIP OF PATHOLOGY AND FUNCTIONAL DECLINE WITH TAUOPATHY
E Karen, Professor
Columbia University Health Sciencescity: New York country: United States (us)
Grant 1R01NS074874-01 from National Institute Of Neurological Disorders And Stroke
Abstract: In the earliest stages of AD, tangle pathology is limited to the hippocampal formation. As the disease progresses however, pathology is seen in cortical areas and these later stages correlate with the onset of overt dementia. Although the progressive spread of pathology has been mapped in humans, most transgenic mouse models of the disease do not model what is seen in humans due to the use of promoters that drive high level expression of AD-related transgenes in inappropriate, or regionally diverse areas of the brain. To model the initial stages of the disease, and to map the spread of pathology out of the hippocampal formation, we have created a novel line of mice with regionally restricted expression of human tau in parahippocampal/hippocampal regions of relevance to the earliest affected regions in the AD brain. A second mouse model will change the regions in which tau is expressed through injection of tau-containing extract into synaptically connected, and unconnected areas of the brain to allow further insight into the significance of network activity in pathology propagation. Three specific aims will address the following issues 1) if the anatomical progression of pathology out of the entorhinal cortex supports the hypothesis that tau pathology spreads transynaptically. 2) the spatio-temporal relationship between basal metabolic function (cerebral blood volume assessed by functional imaging) and pathological progression to test the hypothesis that functional decline is associated with accumulation of pathological tau species in vulnerable brain regions and 3) the spatio-temporal relationship between metabolic function and cognitive impairment, and the relationship with pathological progression to test the hypothesis that cognitive impairment occurs after metabolic dysfunction, when pathology is extensive in extrahippocampal regions. All three measures (neuropathology, metabolic function and cognitive performance) will be assessed relative to each other to provide a spatial and temporal ordering of events. These studies will allow us to not only address a key issue in AD pathobiology - whether transynaptic spread is implicated in propagation of the disease, but mapping the anatomical progression of the disease and correlating it with functional measures of metabolic function (fMRI) and cognitive performance will give insight into spatial and temporal relationships between these measures. These insights could inform on future therapeutic approaches that could prevent the progression of the disease when administered at an early stage. Alzheimer´s Disease is a progressive disease characterized by the accumulation of amyloid/Abeta and tau tangles in defined regions of the brain. In the earliest stages, tangle pathology is limited to the hippocampal formation but as the disease progresses, pathology is seen in cortical areas and these later stages correlate with the onset of overt dementia. Although the progressive spread of pathology has been mapped in humans, most transgenic mouse models of the disease do not model this feature of the disease. To model the initial stages of the disease, and to map the spread of pathology, metabolic dysfunction and cognitive impairment through the brain, we have created a novel line of mice with regionally restricted expression of human tau. Insights from these mice could inform on future diagnostic or therapeutic approaches that could prevent the progression to severe stages
Keywords: a beta peptide; abeta; Address; Affect; Alzheimer; Alzheimer beta-Protein; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s amyloid; Alzheimer`s Disease; Alzheimers Dementia; Alzheimers disease; Amentia; Ammon Horn; Amyloid; Amyloid Alzeheimer`s Dementia Amyloid Protein; amyloid beta; Amyloid Beta-Peptide; Amyloid beta-Protein; Amyloid beta-Protein, Alzheimer`s; Amyloid Fibril Protein (Alzheimer`s); Amyloid Protein A4; Amyloid Substance; amyloid-b protein; Area; area striata; Area striata; Area striata structure; beta amyloid fibril; Biochemical; Blood Volume; Brain; Brain region; Cell Body; cell body (neuron); Cells; Cerebrum; Cognitive; Cognitive decline; Cognitive Disturbance; cognitive dysfunction; cognitive function; Cognitive function abnormal; Cognitive Impairment; cognitive loss; cognitively impaired; conformer; Cornu Ammonis; Cortex, Striate; Data; decline in function; Dementia; dementia of the Alzheimer type; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Development; Diagnostic; Disease; Disease Progression; disease/disorder; Disorder; Disturbance in cognition; Dysfunction; Encephalon; Encephalons; Entorhinal Area; Entorhinal Cortex; entorhinal cortex; Event; fMRI; functional decline; functional disability; Functional disorder; Functional Imaging; Functional impairment; Functional Magnetic Resonance Imaging; Future; Goals; hippocampal; Hippocampal Formation; hippocampal subregions; Hippocampus; Hippocampus (Brain); homotypical cortex; Human; Human, General; Impaired cognition; Injection of therapeutic agent; Injections; insight; interest; isocortex; Learning; Lesion; Link; Magnetic Resonance Imaging, Functional; Mammals, Mice; Man (Taxonomy); Man, Modern; Maps; Measures; Memory; Metabolic; Mice; microtubule associated protein tau; microtubule bound tau; microtubule-associated protein tau; microtubule-bound tau; Modeling; mouse model; MRI, Functional; MT-bound tau; Murine; Mus; mutant; Neocortex; neopallium; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; neural cell body; Neurocyte; neurofibrillary degeneration; neurofibrillary lesion; neurofibrillary pathology; Neurofibrillary Tangles; neuronal; neuronal cell body; Neurons; neuropathology; non-human primate; nonhuman primate; novel; Parietal; parietal cortex; Parietal Lobe; Parietal Lobe of the Brain; Pathology; pathophysiology; pathway; Pathway interactions; Performance; Physiologic Imaging; Physiopathology; prevent; preventing; primary degenerative dementia; Primary Senile Degenerative Dementia; Primary visual cortex; Progressive Disease; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); public health relevance; Relative; Relative (related person); Secondary to; senile dementia of the Alzheimer type; soluble amyloid precursor protein; soma; Staging; Striate area; Structure of entorhinal cortex; Synapses; Synaptic; tangle; tau; tau associated neurodegeneration; tau associated neurodegenerative process; tau factor; tau induced neurodegeneration; tau mediated neurodegeneration; tau neurodegenerative disease; tau neuropathology; tau Proteins; tauopathic neurodegenerative disorder; Tauopathies; tauopathy; Testing; Therapeutic; Time; transcytosis; Transgenes; transgenic; Transgenic Mice; Transgenic Organisms; uptake
Relevance: Alzheimer´s Disease is a progressive disease characterized by the accumulation of amyloid/Abeta and tau tangles in defined regions of the brain. In the earliest stages, tangle pathology is limited to the hippocampal formation but as the disease progresses, pathology is seen in cortical areas and these later stages correlate with the onset of overt dementia. Although the progressive spread of pathology has been mapped in humans, most transgenic mouse models of the disease do not model this feature of the disease. To model the initial stages of the disease, and to map the spread of pathology, metabolic dysfunction and cognitive impairment through the brain, we have created a novel line of mice with regionally restricted expression of human tau. Insights from these mice could inform on future diagnostic or therapeutic approaches that could prevent the progression to severe stages
Project start date: 2011-03-01
Project end date: 2016-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-10-067
1R01NS074874-01 (2011): $454153
CONSTRUCTION OF A REFERENCE SEQUENCE DATA SET FOR THE HUMAN MICROBIOME PROJECT
E Karen, Director
J. Craig Venter Institute, Inc.city: Rockville country: United States (us)
Grant 4U54AI084844-03 from Office Of The Director, National Institutes Of Health
Abstract: Human physiology and health is highly dependent on the activities of billions of microorganisms that inhabit multiple niches within and on the human body. Few of these microorganisms have been characterized, in large part because the majority are yet to be cultivated. As such, the impact this vast number of species has on human health remains to be elucidated. This proposal presents the J. Craig Venter Institute´s approach to generating the genomic sequences of a significant number of reference species including bacteria, fungi, viruses and phage that are associated with the human body. We also describe how we will generate metagenomic sequences from DNA samples collected from various body sites of multiple individuals. The specific aims include the sequencing, assembly and annotation of 400 microbial genomes (60 of which will be closed) to provide reference genomes for metagenomic data; characterization of the microbiota from multiple body sites via shotgun sequencing of these samples, and the use of our state-of-the-art assembly and analysis tools to further interpret this data. We will also investigate microeukaryotic diversity, focusing on the 28S rRNA gene and internal transcribed spacer regions. Cell sorting, combined with whole genome amplification will be employed to obtain genomic DNA from previously uncultured prokaryotes. Finally, the dynamic range of expressed RNA from marker genes identified through metagenomic analyses will be interrogated using a novel mRNA transcript capture and amplification approach. This study will be conducted using cutting edge technologies including next generation approaches to sequencing. We will continue outreach and education to research clinicians, and will make all data readily available. Without a doubt, the findings from the proposed study will increase current understanding of the microbial diversity associated with the human body and the impact of these species on health and disease
Relevance: This broad genomic and metagenomic survey of the human microbiome will lay a foundation for future efforts to understand the impact the microbes that inhabit the human body have on human health and disease
Project start date: 2009-05-22
Project end date: 2013-08-31
Budget start date: 9-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-RM-08-001
4U54AI084844-03 (2011): $709235
4U54AI084844-03_7810 (2011): $709235
FOREGUT MICROBIOME IN DEVELOPMENT OF ESOPHAGEAL ADENOCARCINOMA
E Karen, Assistant Professor
New York University School Of Medicinecity: New York country: United States (us)
Grant 5UH3CA140233-03 from Office Of The Director, National Institutes Of Health
Abstract: Esophageal adenocarcinoma (EA), the type of cancer linked to heartburn due to gastroesophageal reflux diseases (GERD), has increased six fold in the past 30 years, which cannot be explained by the usual environmental or host factors. EA is the end result of a sequence of GERD-related diseases, preceded by reflux esophagitis (RE) and Barrett´s esophagus (BE). Our preliminary study in elderly male veterans found two types of microbiotas in the esophagus. Patients who carry the type II microbiota are >15 fold likely to have esophagitis and BE than those harboring the type I microbiota. In a small-scale study, we also found that 3 of 3 cases of EA harbored the type II biota. The findings have opened a new approach to understanding the recent surge in the incidence of EA. Our long-term goal is to identify the cause of GERD sequence. The hypothesis to be tested is that changes in the foregut microbiome are associated with EA and its precursors, RE and BE in GERD sequence. We will examine whether the finding in elderly male subjects also applies to younger as well as female subjects. We will conduct a case control study to demonstrate the microbiome-disease association in every stage of GERD sequence as well as analyze the trend in changes in the microbiome along disease progression toward EA, by two specific aims. Aim 1 is to conduct a comprehensive population survey of the foregut microbiome and demonstrate its association with GERD sequence. Furthermore, spatial relationship between the esophageal microbiota and upstream (mouth) and downstream (stomach) foregut microbiotas as well as temporal stability of the microbiome-disease association will also be examined. Aim 2 is to define the distal esophageal metagenome and demonstrate its association with GERD sequence. Detailed analyses will include pathway-disease and gene-disease associations. Archaea, fungi and viruses, if identified, also will be correlated with the diseases. A significant association between the foregut microbiome and GERD sequence, if demonstrated, will be the first step for eventually testing whether an abnormal microbiome is required for the development of the sequence of phenotypic changes toward EA. If EA and its precursors represent a microecological disease, treating the cause of GERD might become possible, for example, by normalizing the microbiota through use of antibiotics, probiotics, or prebiotics. Causative therapy of GERD could prevent its progression and reverse the current trend of increasing incidence of EA. Esophageal adenocarcinoma, the type of cancer linked to heartburn due to gastroesophageal reflux diseases (GERD), has jumped six folds in the past 30 years, which cannot be explained by the usual environmental or host factors. We intend to characterize the change in the esophageal microbiome (the native bacterial population of the esophagus), in patients at various stages in GERD. If GERD represents a microbiome-related disease, it could be possible to design new antibiotic or probiotic treatment strategies to prevent GERD and reverse the current trend of increasing rate of esophageal adenocarcinoma
Keywords: Age; age group; Anatomy; Antibiotics; Archaea; Barrett Esophagus; Biota; cancer type; Case-Control Studies; design; Development; Disease; Disease Association; Disease Pathway; Disease Progression; disorder risk; Distal; DNA Viruses; Elderly; Endoscopy; Environmental Risk Factor; Esophageal; Esophageal Adenocarcinoma; Esophagitis; Esophagus; Female; fungus; Gastric Acid; Gastroesophageal reflux disease; Gender; Genes; Goals; Grouping; Health; Heartburn; Histology; Hospitals; Incidence; Integration Host Factors; Intestinal Metaplasia; Link; Literature; Logistic Regressions; male; medical schools; Metagenomics; microbial; microbiome; Monitor; New York; novel strategies; Odds Ratio; Oral cavity; Patients; Peptic Esophagitis; Pharmaceutical Preparations; Phenotype; Pilot Projects; Population; population survey; prebiotics; Prevalence; prevent; Primitive foregut structure; Probiotics; Recombinant DNA; Recruitment Activity; Reflux; Research Design; Risk Factors; Sampling; spatial relationship; Staging; Stomach; Symptoms; Teaching Hospitals; Technology; Testing; treatment strategy; trend; Universities; upper GI series; Veterans; Virus
Relevance: Esophageal adenocarcinoma, the type of cancer linked to heartburn due to gastroesophageal reflux diseases (GERD), has jumped six folds in the past 30 years, which can not be explained by the usual environmental or host factors. We intend to characterize the change in the esophageal microbiome (the native bacterial population of the esophagus), in patients at various stages in GERD. If GERD represents a microbiome-related disease, it could be possible to design new antibiotic or probiotic treatment strategies to prevent GERD and reverse the current trend of increasing rate of esophageal adenocarcinoma
Project start date: 2009-05-08
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-RM-08-012
5UH3CA140233-03 (2011): $1457134
DUAL TARGETING OF DNA REPAIR AND P53 PATHWAYS FOR TREATMENT OF BRAIN CANCER
E Karen, Assistant Professor
Indiana Univ-purdue Univ At Indianapoliscity: Indianapolis country: United States (us)
Grant 5R01CA138798-02 from National Cancer Institute
Abstract: Development of efficacious strategies for treatment of glioblastoma multiforme (GBM) remains a significant challenge in both pediatric and adult patients. Some improvements, such as treatment with radiation and temozolomide (TMZ), have led to increased survival. However, the prognosis for brain tumor patients remains poor, and is largely due to the ability of these malignancies to acquire chemoresistance by modulation of p53-regulated signaling pathways that control cell survival. Our long-term goal is to develop therapeutic strategies that sensitize drug- and radiation-resistant brain tumors to therapy. In this proposal, we will investigate the efficacy of a novel combination therapy that targets the HDM2/p53 network and DNA repair. Inhibition of HDM2 interactions with key signaling molecules-p53, p73a, and HIF1a-by the small molecule inhibitor, nutlin3, can modulate their downstream effector function. Depending on the cell type studied, exposure to the HDM2 antagonist can lead to cell cycle arrest, senescence, apoptosis, decreased migration, and attenuation of VEGF production. To what extent TMZ and radiation in combination with nutlin3 can modulate these critical intracellular targets has not been studied. Our data indicate that nutlin3 can significantly potentiate TMZ- and radiation-mediated cytotoxicity in glioblastoma cells in vitro. In addition, nutlin3 also enhanced TMZ-mediated glioblastoma cell kill in an ectopic xenograft model. Our overall objective is to develop efficacious treatment strategies that kill brain tumor cells but not normal cells. For drug efficacy studies, ectopic and orthotopic glioblastomas will be established in NOD/SCID/IL2Rnull mice. A panel of established glioblastoma cell lines and early passaged glioblastoma primary cultures that differ in EGFR gene amplification, p53 status (wild-type or mutant), HDM2 status, MGMT expression, and sensitivities to TMZ and irradiation will be utilized. Real-time bioluminescence imaging will be utilized to serially monitor glioblastoma progression over time. Our central hypothesis is that nutlin3 potentiates the TMZ- and/or radiation-induced DNA damage response by perturbing HDM2-mediated regulation of key signaling molecules, and leads to increased glioblastoma cell death in vivo. To test this hypothesis, the following specific aims are proposed 1) Develop therapeutic regimens and validate intracellular target modulation mediated by inhibition of HDM2-protein interactions during exposure to DNA-damaging agents 2) Assess in vivo the outcome of modulating HDM2-dependent signaling to increase therapeutic efficacy of TMZ- and/or radiation- mediated DNA damage. 3) Employ intracranial GBM xenograft models in combination with serial real- time bioluminescence imaging to monitor therapeutic impact of modulating HDM2-dependent signaling in combination with TMZ- and/or radiation-mediated DNA damage. The treatment strategies investigated here will use clinically relevant in vivo models and novel multi-targeting approaches and have the potential to improve treatment efficacy and quality of life for patients with GBM. The central hypothesis is that the HDM2 antagonist, nutlin3, potentiates TMZ and/or radiation-induced DNA damage response by perturbing HDM2-mediated regulation of key signaling molecules and leads to increased glioblastoma cell death in vivo. The underlying mechanisms of glioblastoma cell kill will be determined and ectopic and orthotopic brain tumor models will be used to evaluate in vivo efficacy
Keywords: Address; Adult; Affect; Aftercare; Alkylating Agents; angiogenesis; Apoptosis; attenuation; base; Bioluminescence; Brain; Brain Neoplasms; Cancer Patient; cancer therapy; cancer type; Cell Cycle Arrest; Cell Death; cell killing; Cell Line; Cell Survival; cell type; Cells; Chemosensitization; Childhood; Chimeric Proteins; Clinical; clinically relevant; combinatorial; Combined Modality Therapy; conventional therapy; Cytotoxic agent; cytotoxicity; Data; Development; DNA Damage; DNA Repair; DNA Repair Pathway; DNA repair protein; Drug Combinations; drug efficacy; Drug Kinetics; Drug toxicity; E2F1 gene; effective therapy; EGFR Gene Amplification; experience; Exposure to; Frequencies (time pattern); Genotoxic Stress; Glioblastoma; Goals; Growth; Human; human MDM2 protein; hypoxia inducible factor 1; Image; Imaging technology; Implant; improved; In Vitro; in vivo; in vivo Model; inhibitor/antagonist; Investigation; irradiation; Killings; Kinetics; Laboratories; Lead; Lentivirus Vector; Luciferases; Malignant neoplasm of brain; Malignant Neoplasms; Mediating; migration; Modeling; Molecular Profiling; Monitor; Mus; mutant; neoplastic cell; Normal Cell; Normal tissue morphology; novel; O(6)-Methylguanine-DNA Methyltransferase; Operative Surgical Procedures; Outcome; outcome forecast; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Population; Positioning Attribute; Production; public health relevance; Quality of life; Radiation; Radiation Induced DNA Damage; Radiation Oncology; Radiation-Sensitizing Agents; Refractory; Regimen; Regulation; Research; Resistance; response; senescence; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; small molecule; standard care; stem; success; temozolomide; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Treatment Efficacy; Treatment outcome; Treatment Protocols; treatment response; treatment strategy; tumor; tumor progression; tumor xenograft; ubiquitin-protein ligase; Vascular Endothelial Growth Factors; Xenograft Model
Project start date: 2010-07-15
Project end date: 2015-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PAS-08-048
5R01CA138798-02 (2011): $312326
EFFECTS OF EXERCISE AND COGNITIVE TRAINING ON EXECUTIVE FUNCTION IN PARKINSON´S
E Karen, Assistant Professor
Baltimore Va Medical Centercity: Baltimore country: United States (us)
Abstract: Deficits in cognitive-EF (executive function) are frequently seen early in PD and progress, resulting in disruption of daily activities. People with PD are often impaired in real life situations in which more than one activity needs to be performed at a time. This Merit Review Proposal compares efficacy of two rehabilitation interventions to reduce cognitive-EF deficits and improve both dual tasking (DT) abilities and instrumented activities of daily living (IADLs) in veterans and others with Parkinson´s Disease (PD). Interventions are(1) a treadmill exercise program with aerobic training (TAEX) (2) a computerized cognitive training program (TCOG). These two rehabilitation regimens will be compared alone and in combination. The study will provide insight into individual and synergistic effects of these interventions and optimal rehabilitation strategies to improve cognitive and functional performance in PD. We hypothesize that combined 3 months of TAEX+TCOG will be more effective to improve cognitive- EF domains, DT performance, and IADLs compared to either of these regimens alone. Because the natural history of EF decline has not been well characterized in PD with different levels of the disease, we will also employ a delayed entry control group that will further enable us to determine whether any of these treatment modalities is more effective than no intervention. We hypothesize that treatment effects of TAEX + TCOG will be retained for a period of 3 months following the intervention. The specific aims of this project are (1) To compare the efficacy of TAEX versus TCOG versus TAEX + TCOG as interventions to improve EF in PD (2) To compare the efficacy of TAEX versus TCOG versus TAEX + TCOG as interventions to improve Dual Task (DT) performance in PD (3) To investigate whether improvement in DT performance translates into improved ability to conduct Instrumental Activities of Daily Living (IADLs). Each intervention will last 3 months. The TAEX intervention will consist of progressive treadmill exercise with aerobic training 3 times/week, with a conservative start of 20 mins. per session progressive to 45 mins. The TCOG intervention will consist of computerized cognitive training 3 times/week for 30 mins. The combined TAEX + TCOG intervention will last 1 hour and 30 mins. Subjects in the control group (delayed entrance) will go through a period of no intervention for 3 month baseline. During baseline they will not exercise or participate in any cognitive training activities. Following the baseline period they will be assigned to one of the intervention groups and will go through the exercise protocol of their respective group. Outcome measures will include (1) Neuropsychological assessment with paper-and-pencil and computer- based tests of EF, (2) DT with a "walking while talking" paradigm, (3) daily activity measures (4) Psychiatric Measures (5) Cardiorespiratory Function Measures. Currently there is no effective treatment for the specific cognitive deficits caused by PD. No studies have investigated the potential benefits of rehabilitation strategies to improve such deficits. The proposed work will help generate new knowledge about rehabilitation models for cognitive impairment and cognitive-related disability in patients with PD. They will pave the way for multi-center clinical trials, producing efficacy data on which clinical practice can be based. Parkinson´s Disease (PD) affects men with a higher frequency than women. Onset of PD is generally between the fifth and seventh decades; 3 percent of people over 65 have PD. Given that the VA population is predominantly male and aging, significant numbers of veterans will develop PD in the coming years. Testing practical interventions that could slow decline in cognitive abilities and consequent impairments of daily function carries a broad significance for chronically disabled individuals with PD. There are not proven treatments for cognitive deficits in this population. The current study will investigate the effectiveness of two different rehabilitation strategies and the potential synergy between them to improve cognitive function and cognitive-related disability in veterans with Parkinson´s Disease. The proposed studies could lead to novel clinical interventions for impairment due to cognitive dysfunction in PD
Project start date: 2010-10-01
Project end date: 2014-09-30
Budget start date: 1-OCT-2010
Budget end date: 30-SEP-2014
PFA/PA: RFA-RX-09-003
1I01RX000277-01 (2011): $0
DEVELOPMENT OF BIMANUAL COORDINATION OF EARLY CHILDHOOD
E Karen, Associate Professor
Spelman Collegecity: Atlanta country: United States (us)
Grant 5R15HD047203-03 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Bimanual coordination is important to adaptive human functioning; yet our understanding of its development and relation to developmental disorders is incomplete. This project will adopt a dynamic systems approach to examining bimanual competence in children between the ages of 15 and 27 months, a target group whose activity has previously been under-represented in the literature. The project´s methodology will include a longitudinal study of an easily elicited rhythmic percussive behavior, drumming. Individual developmental trajectories will be mapped according to the principles and methods of developmental systems analysis. Additionally, introduction of auditory or human models will allow the investigator to determine whether reducing the self-regulatory requirements placed on the child increases the stability of bilateral rhythmic behavior at different points in the development of this skill. It is hypothesized that such reduction of the self-regulatory requirements will indeed increase stability of the drumming behavior at transitional points at which the behavior shifts from one point to another. Kinematic analysis will allow microgenetic as well as ontogenetic data to be reported at both the individual and aggregate level, in keeping with dynamic systems approaches to analysis. It is believed that this project will inaugurate a productive program of study that will allow in-depth examination of the motoric, cognitive, and contextual factors that contribute to bimanual competence in young children, as well as lead to potential early diagnostic and intervention applications for atypical developmental conditions. Additionally, it will provide research-training opportunities for several students who are under-represented minority women. It is important to understand the developmental pathways typically experienced by children with respect to bimanual skills, particularly during the first years of life. Children in this age range are undergoing rapid growth in skill development, and early childhood represents a critical point for diagnosis of developmental disorders prior to entry into school. Because bimanual competence is so integral to our daily activity as humans, and because investigators have discovered links between atypical bimanual coordination patterns and developmental disorders, it is believed that this project may ultimately lead to useful nonlinguistic early diagnostic and intervention tools for children at risk for developmental disorders
Keywords: 0-11 years old; Adopted; Age; Application Context; Auditory; Basic Research; Basic Science; Behavior; Bilateral; Child; Child Youth; children; Children (0-21); clinical Diagnosis; Cognitive; Comment; Comment (PT); Comment [Publication Type]; Commentary; Commentary (PT); Competence; contextual factors; Data; Development; developmental disease/disorder; developmental disorder; Diagnosis; Diagnostic; early childhood; Editorial Comment; Editorial Comment (PT); experience; Feedback; Foundations; Goals; heavy metal lead; heavy metal Pb; Human; Human, Child; Human, General; Individual; innovate; innovation; innovative; Intervention; Intervention Strategies; interventional strategy; Investigators; kinematics; Lead; Life; Link; Literature; long-term study; Longitudinal Studies; Man (Taxonomy); Man, Modern; Maps; Membrum superius; Method LOINC Axis 6; Methodology; Methods; Modeling; Motor; One Step; One-Step dentin bonding system; pathway; Pathway interactions; Pattern; Pb element; programs; Programs (PT); Programs [Publication Type]; Published Comment; rapid growth; Reporting; Research; Research Personnel; Research Training; Researchers; Risk; Schools; skills; Students; Study Section; System; System, LOINC Axis 4; Systems Analyses; Systems Analysis; tool; under-represented minority; Underrepresented Minority; underserved minority; Upper Extremity; Upper Limb; Viewpoint; Viewpoint (PT); Woman; youngster
Project start date: 2008-02-01
Project end date: 2012-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2012
PFA/PA: PA-06-042
5R15HD047203-03 (2010): $64843
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