GENES MEDIATING INNATE IMMUNE SUPPRESSION BY HYPERCAPNIA IN MAMMALS AND FLIES
H Peter
Northwestern Universitycity: Evanston country: United States (us)
Grant 1R01HL107629-01A1 from National Heart, Lung, And Blood Institute
Abstract: Hypercapnia, elevation of PCO2 in blood and tissue, commonly occurs in severe acute and chronic lung disorders, such as chronic obstructive pulmonary disease (COPD). Patients with advanced COPD frequently develop bacterial lung infections, and hypercapnia is a risk factor for mortality in such individuals, as in those with community-acquired pneumonia. We have shown that hypercapnia suppresses transcription of innate immune response genes required for host defense in human, mouse and Drosophila cells, and increases mortality due to bacterial infections in mice and Drosophila. These findings suggest that hypercapnia is not simply a marker of advanced lung disease, but plays a causal role in poor clinical outcomes by increasing susceptibility to infection. Our data also strongly suggest that hypercapnia inhibits innate immunity and host defense by pathway(s) conserved from Drosophila to mammals. Because the molecular mediator(s) of hypercapnic immune suppression are undefined, we conducted a genome-wide RNAi screen in cultured Drosophila cells, which identified ~140 genes required for hypercapnic suppression of antimicrobial peptide (AMP) genes. The 5 most potent of these candidate CO2-mediators encode the zinc finger homeodomain transcription factor, Zfh2; a histone deactylase; a histone methyltransferase; a chromatin-associated Ig-repeat protein; and a Rac-interacting protein. of these genes were previously known to have immunoregulatory function. Exciting new data indicate that mutations in zfh2 protect adult Drosophila against CO2-induced host defense defects. Thus, we hypothesize that Zfh2 and the proteins encoded by the other 4 candidate genes are components of pathway(s) by which hypercapnia suppresses innate immune gene expression and host defense in Drosophila, and that the mammalian orthologs of these genes mediate hypercapnic suppression of innate immune/host defense genes in mouse and human phagocytes. In the case of Zfh2 and its mammalian orthologs, ZFHX3 and ZFHX4, we further hypothesize that hypercapnia alters their abilities to bind target gene promoters or components of the NF-B transcriptional complex, or modifies the transcriptional activity of these factors, thereby decreasing expression of specific innate immune/host defense genes. In the proposed studies, we will test these hypotheses in vitro using cultured fly, mouse and human macrophages, and in vivo using adult Drosophila and lung inflammatory cells obtained from mice with Pseudomonas aeruginosa pneumonia. These studies will for the first time define components of conserved pathway(s) by which hypercapnia impairs innate immunity and host defense, and determine their mechanisms of action. The results should lay the basis for future studies aimed at preventing hypercapnic immune suppression in patients with advanced lung disease. Hypercapnia, or elevation of the level of carbon dioxide (CO2) in the body, commonly develops in people with advanced lung diseases. These individuals more frequently develop lung infections and have an increased risk of dying. This project will determine how hypercapnia leads to more and worse infections by determining the function of the first identified mediator of hypercapnic immune suppression, and by identifying additional components of immunosuppressive CO2-response pathways
Keywords: Acute; Adult; Adverse effects; antimicrobial peptide; Bacterial Infections; bacterial resistance; base; Binding (Molecular Function); Blood; Candidate Disease Gene; Carbon Dioxide; Cause of Death; CCL2 gene; Cells; Chromatin; Chronic; Chronic Obstructive Airway Disease; Clinical; Communities; Complex; Data; Defect; Drosophila genus; fly; Foundations; Future; Gene Components; Gene Expression; Gene Targeting; Genes; Genetic Transcription; genome-wide; histone methyltransferase; Histones; homeodomain; Homologous Gene; Host Defense; Human; Hypercapnia; Immune; Immune Response Genes; Immunosuppressive Agents; In Vitro; in vivo; Individual; Infection; Inflammatory; Interleukin-6; Lung; Lung diseases; macrophage; Mammals; Mediating; Mediator of activation protein; Molecular; Mortality Vital Statistics; mouse model; Mus; Mutation; Natural Immunity; Natural immunosuppression; Orthologous Gene; Outcome; p65; Pathway interactions; Patients; Phagocytes; Play; Pneumonia; Predisposition; prevent; Promotor (Genetics); Proteins; Pseudomonas aeruginosa; Regulator Genes; response; Risk; Risk Factors; RNA Interference; Role; System; Testing; Time; Tissues; TNFRSF5 gene; transcription factor; Validation; Zinc Fingers
Relevance: Hypercapnia, or elevation of the level of carbon dioxide (CO2) in the body, commonly develops in people with advanced lung diseases. These individuals more frequently develop lung infections and have an increased risk of dying. This project will determine how hypercapnia leads to more and worse infections by determining the function of the first identified mediator of hypercapnic immune suppression, and by identifying additional components of immunosuppressive CO2-response pathways
Project start date: 2011-12-15
Project end date: 2015-11-30
Budget start date: 15-DEC-2011
Budget end date: 30-NOV-2012
1R01HL107629-01A1 (2012): $370150
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to H Peter
CELL AND MOLECULAR BIOLOGICAL ANALYSIS OF SYNAPTOPODIN
H Peter, Associate Professor Of Medicine
Massachusetts General Hospitalcity: Boston country: United States (us)
Grant 2R01DK057683-14A1 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Podocyte foot processes and the interposed slit diaphragms form the final barrier to protein loss, explaining why podocyte injury is typically associated with marked proteinuria. The highly dynamic foot process actin cytoskeleton is linked to the slit diaphragm and proteins regulating podocyte actin dynamics are therefore of critical importance for structural maintenance and sustained function of the glomerular filter. Synaptopodin was first described by the P.I. as the founding member of a novel class of actin associated proteins highly expressed in podocytes and telencephalic dendrites Based on the data obtained with this grant, we established that synaptopodin stabilizes the kidney filter by blocking the re-organization of the podocyte actin cytoskeleton into a migratory phenotype We also established that the calcineurin inhibitor cyclosporine A protects against proteinuria by stabilizing synaptopodin steady-state levels in podocytes. Here we propose to test our central hypothesis that the activation of the tyrosine kinase Src in podocytes contributes to the pathogenesis of proteinuria by promoting the degradation of synaptopodin, thereby shifting the balance of Rho GTPase activity towards pro-migratory Rac1 signaling. To test this hypothesis we propose the following three Specific Aims. The first Aim will define the molecular mechanism by which Src induced degradation of synaptopodin affects the actin cytoskeleton in podocytes. Specific Aim two seeks to explore the regulation of Rac1 activation in podocytes by synaptopodin. The third Aim will establish the contribution of synaptopodin degradation to the pathogenesis of podocyte foot process effacement proteinuria in vivo. If our hypothesis is correct, the work proposed here will have broad significance because it will provide us with a better understanding of the biological mechanism underlying the dynamic re-organization of the podocyte actin cytoskeleton in normal and proteinuric kidneys. This should in the long-term enable us to develop novel, selective podocyte- protective therapies that tackle proteinuria by promoting the synaptopodin-dependent preservation of the normal foot process architecture. Our work, funded by this grant, has revealed a novel synaptopodin-dependent signaling pathway for the regulation of the podocyte function in health and disease. This detailed understanding of a synaptopodin-specific anti-proteinuric effect validates the podocyte as target of choice for the treatment of proteinuria. The goal of this application is to further define the molecular mechanisms whereby the stabilization of synaptopodin protein expression protects against proteinuria, thereby paving the road for the development of novel anti-proteinuric treatment options for which there is a critical need in the clinic. !
Keywords: Actins; Affect; Albuminuria; Angiotensin II; Architecture; base; Binding (Molecular Function); Biological; Biological Preservation; Calcineurin; Calcineurin inhibitor; Cathepsin L; cell body (neuron); Cells; Characteristics; Clinic; Complex; Cyclosporine; Cytoskeleton; Data; Dendrites; Development; Disease; DNA Sequence Rearrangement; Dominant-Negative Mutation; Drosophila sli protein; Equilibrium; Filtration; Foot Process; Functional disorder; Funding; Gene Silencing; Gene Transfer; glomerular basement membrane; glomerular function; Goals; Grant; Guanine; Guanine Nucleotide Exchange Factors; Health; In Vitro; in vivo; Injury; Kidney; Kidney Diseases; Lead; Left; Link; Maintenance; Mediating; member; Modeling; Molecular; Mus; Mutation; novel; Pathogenesis; Pattern; Phenotype; podocyte; prevent; Process; Production; protein expression; Proteins; Proteinuria; Publishing; Reactive Oxygen Species; Regulation; Resistance; rho GTP-Binding Proteins; Signal Pathway; Signal Transduction; slit diaphragm; src-Family Kinases; Stress Fibers; synaptopodin; Testing; Work
Relevance: Our work, funded by this grant, has revealed a novel synaptopodin-dependent signaling pathway for the regulation of the podocyte function in health and disease. This detailed understanding of a synaptopodin-specific anti-proteinuric effect validates the podocyte as target of choice for the treatment of proteinuria. The goal of this application is to further define the molecular mechanisms whereby the stabilization of synaptopodin protein expression protects against proteinuria, thereby paving the road for the development of novel anti-proteinuric treatment options for which there is a critical need in the clinic. !
Project start date: 2000-04-01
Project end date: 2016-05-31
Budget start date: 22-SEP-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-10-067
2R01DK057683-14A1 (2011): $380987
ALZHEIMER DISEASE BIOMARKERS IN LENS
H Peter, Associate Professor
Univ Of Med/dent Of Nj-nj Medical Schoolcity: Newark country: United States (us)
Grant 5R01EY015855-04 from National Eye Institute
Abstract: Our work has demonstrated that fundamental neuron-specific cell biology processes that are focused on the Alzheimer beta-amyloid precursor protein (AbetaPP) are shared in the lens to a striking degree, and provided evidence that Abeta pathology is a key element in cataract formation similar to Alzheimer´s disease (AD). Further, studies from our lab and recently others indicate that Abeta pathology in age-related cataract has a remarkably close association with corresponding changes in Abeta pathology in the brain in AD patients, and in animal models. These associations are consistent with an extensively shared biological diathesis for stress during aging in lens and brain and were indicated by our original studies. Now we will investigate the production of specific forms of Abeta pathology in the lens during early disease stages of cataract formation, and will also characterize its relationship with the onset and development of corresponding changes in Abeta pathology in brain. Specifically, we will characterize novel lens Abeta biomarkers we recently identified in the lens and explore their use for the early diagnosis of cataract, and investigate the use of these biomarkers for monitoring associated changes occurring in brain. Our second major goal is also to work to develop our recent novel application of sensitive laser-based technology to detect these Abeta biomarkers in the lens for the diagnosis of early stages of cataract, and will determine its ability to inform about related changes in the brain. This instrument is already providing us with a critical new research tool to help us understand the role of AD pathology in cataracts and relationship with brain. This work has already led to an understanding that ´workhorse´ models in AD research also provide important models of age-related cataract. Our goal is to rigorously characterize Abeta biomarker increases in lens to understand their role in early cataractogenesis in human lens and our animal model, and to investigate onset of production in lens with onset of corresponding pathology in brain. This strictly non-invasive technology has significant potential to detect early stages of cataract prior to formation of significant light scattering or protein aggregation that presently are hallmarks of cataract diagnosis and efforts to monitor changes in brain. These studies build on our earlier studies to understand the role of AbetaPP and Abeta in the lens which are already providing a new and specific conceptual basis for understanding cataract and its links with the brain
Keywords: 21+ years old; a beta peptide; abeta; Adult; adult human (21+); Age; age dependent; age related; Aging; Alzheimer; Alzheimer beta-Protein; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s amyloid; Alzheimer`s Disease; Alzheimers Dementia; Alzheimers disease; Amyloid; Amyloid A4 Protein Precursor; Amyloid Alzeheimer`s Dementia Amyloid Protein; amyloid beta; Amyloid Beta-Peptide; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid beta-Protein, Alzheimer`s; Amyloid Fibril Protein (Alzheimer`s); amyloid precursor protein; Amyloid Protein A4; Amyloid Protein Precursor; Amyloid Substance; amyloid-b protein; Animal Model; Animal Models and Related Studies; base; beta amyloid fibril; Biological; biomarker; Brain; Cataract; cataractogenesis; cataractous lenses; cell biology; Cellular biology; Characteristics; Copper; Cu element; Culturing, in vitro Organ; Culturing, in vitro Vertebrate, Organ; dementia of the Alzheimer type; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Deposit; Deposition; Detection; Development; Diagnosis; Diagnostic; Diathesis; Dietary Cholesterol; Disease; disease classification; disease diagnosis; disease phenotype; Disease susceptibility; disease/disorder; disease/disorder classification; disease/disorder proneness/risk; Disorder; disorder classification; Dysfunction; early detection; Early Diagnosis; Electromagnetic, Laser; Embryo Development; Embryogenesis; Embryonic Development; Employee Strikes; Encephalon; Encephalons; Event; Functional disorder; Funding; Goals; heavy metal lead; heavy metal Pb; Human; human disease; Human, Adult; Human, General; In element; In Situ; Indium; insight; instrument; instrumentation; Instrumentation, Other; Investigators; Lasers; Lead; lens; Lens Diseases; lens disorder; liability to disease; light scattering; Link; Mammals, Rabbits; Man (Taxonomy); Man, Modern; Measures; metal complex; Metals; Methods; model organism; Modeling; Molecular; Monitor; mouse model; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; neuronal; Neurons; new diagnostics; next generation diagnostics; Non-Invasive Cancer Detection; Non-Invasive Detection; nosology; novel; novel diagnostics; Organ Culture; Organ Culture Techniques; Oryctolagus cuniculus; Oxidative Stress; Pathology; pathophysiology; Patients; Pb element; Peptides; Physiopathology; prevent; preventing; primary degenerative dementia; Primary Senile Degenerative Dementia; Process; Production; programs; Programs (PT); Programs [Publication Type]; protein aggregation; Protein Precursors; protein structure; Rabbit, Domestic; Rabbits; Radiation, Laser; Raman spectrometry; Raman Spectroscopy; Raman Spectrum Analysis; Research; Research Personnel; Researchers; Role; Senescence; senescent; Senile Cataract; senile dementia of the Alzheimer type; social role; soluble amyloid precursor protein; Spectroscopy; Spectroscopy, IR/UV/Raman; Spectrum Analyses; Spectrum Analysis; Spectrum Analysis, Raman; Staging; Stress; Strikes; Strikes, Employee; Technology; Time; tool; transgenic; Transgenic Organisms; Work
Project start date: 2007-04-01
Project end date: 2012-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2012
5R01EY015855-04 (2010): $269033
RETINOID AND CAROTENOID DEPLETION IN PATIENTS AT HIGH-RISK FOR LIVER CANCER
H Peter, Director, Pathology Research
University Of Illinois At Chicagocity: Chicago country: United States (us)
Grant 5R21CA131787-02 from National Cancer Institute
Abstract: Median survival from a hepatocellular cancer (HCC) diagnosis is only 8 months; therefore, effective prevention strategies are a high priority. Due to the epidemic of hepatitis C in the 1960´s-70´s, incidence has increased; approximately 3.2 million people are chronically infected and their annual incidence of HCC is 3-4%. Fortuitously, persons at high-risk can easily be identified - virtually all who develop HCC first have cirrhosis or chronic hepatitis, often for years. Oxidative stress due to chronic inflammation is a dominant force in the progression of chronic liver disease (CLD) and subsequent HCC. Therefore, deficiencies in dietary antioxidants such as retinoids and carotenoids, which previously have been reported in CLD, may constitute a major modifiable risk factor. This hypothesis is supported by numerous animal model and epidemiological studies. However, before safe and effective clinical trials aimed at repleting vitamin A and carotenoid stores in high-risk patients can be designed, we need exploratory studies to a) determine the prevalence and determinants of retinoid-carotenoid depletion in well-characterized subgroups of patients typically seen in the U.S., b ) identify optimal biomarkers of oxidative stress that can serve as surrogate endpoints in early trials, and c) determine how biomarkers in serum and urine relate to antioxidant levels in the liver itself and to tissue markers of pre-neoplastic change. We propose cross-sectional studies among CLD patients undergoing liver biopsy at UIC and the University of Chicago, to address these Specific Aims 1. Identify key predictors of serum antioxidant levels in patients with CLD, 2. Quantify the association between systemic measures of oxidative stress (blood, urine) and low retinoid/carotenoid status in CLD, and 3. Quantify the relationship between retinoid/carotenoid levels in liver vs. serum, and determine whether concentrations in liver are associated with pre-neoplastic changes in the same tissue. To address the first 2 aims we will enroll 140 patients (100 with CLD due to hepatitis C and 40 normal controls) and obtain medical, lifestyle and diet data, as well as blood and urine samples. Normal controls will include 10 subjects providing tissue by partial hepatectomy for benign conditions. For Aim 1 we will test the importance of multiple factors (poor diet, stage of CLD, smoking, insulin resistance, age and race) as independent predictors of serum antioxidant levels. For Aim 2, we will measure oxidative damage to DNA via 8OHdG in urine (oxidized, excreted DNA bases) and the comet assay (DNA strand breaks in lymphocytes) to test the association of these markers with serum antioxidant levels. For Aim 3, we will measure retinoid/carotenoid levels in liver tissue and relate that to biomarkers of oxidative stress and pre-neoplastic change (hyperproliferation, DNA damage, nuclear aberration) in liver tissue. Completion of the proposed work will lead directly to full-scale proposals for Phase II trials in CLD patients, with tissue endpoints and either dietary or supplement interventions. The proposed project is part of an effort to find safe and effective ways to prevent liver cancer, through correcting deficiencies in two important classes of dietary antioxidants retinoids (vitamin A) and carotenoids (2-carotene, lycopene). Persons with chronic liver disease are at very high risk for liver cancer, and it has been observed that they have retinoid/carotenoid depletion, for a variety of possible reasons. Before we can properly design prevention trials with the right intervention, the right target population and the right endpoints, we need preliminary studies for guidance, such as we have proposed
Keywords: Address; Affect; Age; Alcohol consumption; Alcohols; All-Trans-Retinol; American; Animal Model; Antioxidants; base; Benign; biomarker; Blood; cancer diagnosis; cancer prevention; Carotene; Carotenoids; Catabolism; Cell Proliferation; Chemoprevention; Chemopreventive Agent; Chicago; Chronic; Chronic Hepatitis; Cirrhosis; Clinic; Clinical Trials; Comet Assay; Cross-Sectional Studies; Data; design; Development; Diabetes Mellitus; Diet; dietary antioxidant; Dietary intake; Dietary Intervention; DNA; DNA Damage; DNA strand break; Dose; Eligibility Determination; Enrollment; Epidemic; Epidemiologic Studies; Esters; F2-Isoprostanes; Failure (biologic function); Formalin; glucose metabolism; Hepatic; Hepatic Tissue; Hepatitis C; Hepatology; Hepatotoxicity; High Prevalence; high risk; Homeostasis; improved; Incidence; Inflammation; Insulin Resistance; Intervention; Intestinal Absorption; Knowledge; Lead; Life Expectancy; Life Style; Link; Lipid Peroxidation; Lipids; Liver; liver biopsy; Liver diseases; Low Income Population; lycopene; Lymphocyte; Malignant neoplasm of liver; Measures; Medical; Metabolism; Micronutrients; Minority Groups; Modeling; modifiable risk; Morbidity - disease rate; Mortality Vital Statistics; neoplastic; Normal Range; Nuclear; Oral; Organ; Outcome; oxidative damage; Oxidative Stress; Partial Hepatectomy; Participant; Patients; Persons; Phase II Clinical Trials; Plasma; Play; Preneoplastic Change; Prevalence; prevent; Prevention; Prevention strategy; Primary carcinoma of the liver cells; Process; public health relevance; Race; randomized trial; Recording of previous events; Relative (related person); Reporting; response; Retinoids; Retinol Binding Proteins; Risk; Risk Factors; Role; S-Phase Fraction; Sampling; Serum; Severities; Smoking; smoking cessation; Staging; Subgroup; success; Supplementation; Surrogate Endpoint; Target Populations; Testing; Therapeutic; Tissues; Universities; urinary; Urine; Vitamin A; Work
Relevance: (RELEVANCE) The proposed project is part of an effort to find safe and effective ways to prevent liver cancer, through correcting deficiencies in two important classes of dietary antioxidants: retinoids (vitamin A) and carotenoids (¿-carotene, lycopene). Persons with chronic liver disease are at very high risk for liver cancer, and it has been observed that they have retinoid/carotenoid depletion, for a variety of possible reasons. Before we can properly design prevention trials with the right intervention, the right target population and the right endpoints, we need preliminary studies for guidance, such as we have proposed
Project start date: 2009-09-04
Project end date: 2012-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2012
PFA/PA: PA-06-295
5R21CA131787-02 (2010): $174110
VALIDATION OF DIGITAL MORPHOMETRY FOR CANCER RISK IN BENIGN PROSTATE BIOPSIES
H Peter, Director, Pathology Research
University Of Illinois At Chicagocity: Chicago country: United States (us)
Grant 1R01CA155301-01 from National Cancer Institute
Abstract: In the PCPT and REDUCE trials, finasteride and dutasteride significantly reduced the detection of prostate cancer (PCa) by 23 and 25% respectively, and thus established that 51-reductase inhibitors (5ARI) are the first class of drugs proven as chemopreventive agents for PCa. The actual efficacy of these drugs varies among individuals, even after considering compliance with the prescribed dosage. Better understanding of the basis for sensitivity to 5ARI chemoprevention will 1) pave the way for development of better-tolerated and more effective agents that exploit this established mechanism, 2) allow clinicians to target responsive men, thus reducing the cost and morbidity of life-long dosage, and 3) validate specific tissue biomarkers as surrogate endpoints for Phase II trials. Our preliminary data based on direct DNA staining suggest that nuclear morphometric features that characterize 5ARI response may also define a field effect that predicts PCa in untreated men with negative biopsies. REDUCE, which was completed in 2009, provides a unique opportunity to address these questions because intermediate, on-study biopsy samples (mandatory at Years 2 and 4) were collected. Previous research indicated that 5ARIs (at higher doses for short periods) produce changes in benign prostate that resemble incomplete atrophy. Our overall goal is to apply cutting- edge imaging approaches, incorporating machine-learning for pattern recognition and multispectral analysis, to the development and validation of intermediate endpoint biomarkers in benign tissue that characterize the response to 5ARI chemoprevention as well as the risk of PCa among men with negative biopsies. We will obtain Year 2 slides and tissue blocks from a random sample of REDUCE participants with various outcomes. Aim 1 To determine the effects of dutasteride (vs. placebo) on both nuclear and architectural features in benign tissue. Aim 2 To determine whether a multivariable treatment-response score differs between subjects who develop PCa while on dutasteride and those who do not, and, Aim 3 To determine the magnitude of association between nuclear phenotype in benign biopsies, and subsequent risk of PCa in untreated men at elevated risk. Altogether, we will use 3 techniques to assess cytomorphology a) a morphometric score based on nuclear size, shape and texture, b) expression -via quantum dot imaging - of p300 and nucleolin (two proteins with major effects on chromatin pattern and nuclear morphology) and c) mapping of architectural features (e.g., epithelial area and height) via trainable software. This will be the first work to relate the cytomorphological effects of a 5ARI, given at a chemopreventive dose level for a lengthy period, to subsequent cancer occurrence. The results will have implications for chemoprevention research and clinical practice, including the large number of U.S. men who remain at risk following a negative prostate biopsy. Prostate cancer is the most commonly diagnosed form of cancer in men and strategies to prevent or inhibit its development are critically needed. The goal of the proposed research is to validate new tissue imaging methods for determining risk of prostate cancer among men who have a negative prostate biopsy and for identifying those who are most likely to benefit from life-long chemopreventive drugs
Keywords: active method; Address; Androgens; Area; Atrophic; base; Benign; Biological Assay; biomarker; Biopsy; Biopsy Specimen; cancer cell; cancer risk; Chemoprevention; Chemopreventive Agent; Chromatin; clinical practice; Computer software; cost; Data; Databases; deprivation; Detection; Development; Diagnosis; digital; DNA; dosage; Dose; drug efficacy; Dutasteride; EP300 gene; Epithelial; Finasteride; Gene Expression; Gland; Goals; Height; Image; Image Analysis; imaging modality; indexing; Individual; inhibitor/antagonist; Intention; Life; Machine Learning; Malignant neoplasm of prostate; Malignant Neoplasms; Maps; Measures; member; men; Metric; Microscopy; Morbidity - disease rate; Morphology; morphometry; Nature; Normal Cell; Nuclear; Nuclear Proteins; Nuclear Structure; nucleolin; Outcome; Oxidoreductase; Participant; Pattern; Pattern Recognition; Pharmaceutical Preparations; Phase; phase 3 study; Phase II Clinical Trials; Phenotype; Placebo Control; Placebos; Play; Population; prevent; Prostate; protein expression; Proteins; Quantum Dots; Randomized; Research; Resistance; response; Risk; Role; Sampling; Serum; Shapes; Slide; Staining method; Stains; Surrogate Endpoint; Techniques; Texture; Tissues; treatment response; Validation; Variant; Work
Relevance: Prostate cancer is the most commonly diagnosed form of cancer in men and strategies to prevent or inhibit its development are critically needed. The goal of the proposed research is to validate new tissue imaging methods for determining risk of prostate cancer among men who have a negative prostate biopsy and for identifying those who are most likely to benefit from life-long chemopreventive drugs
Project start date: 2011-09-12
Project end date: 2016-07-31
Budget start date: 12-SEP-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-10-067
1R01CA155301-01 (2011): $343953
ROLE OF IL-6 IN THE PATHOGENESIS OF YERSINIA ENTEROCOLITICA INFECTION
H Peter
University Of Texas Hlth Sci Ctr San Antcity: San Antonio country: United States (us)
Grant 5R01AI067716-05 from National Institute Of Allergy And Infectious Diseases
Abstract: Food and water borne infectious diseases are a significant source of morbidity and mortality world-wide. Children are especially at risk from these infections. Although often assumed to be only a problem in developing areas of the world, bacterial infections of the gastro-intestinal tract remain a serious source of disease in the US. Our long-term goal is to understand both host-response and host pathogen interactions in the gut to Yersinia enterocolitica that lead to resolution of infection or to pathology. Y. enterocolitica is an excellent pathogen to use in our studies as it has served as one of the paradigms of bacterial infectious diseases. In this proposal we expand our studies to look at the role of IL-6 in the modulation of the host response during Y. enterocolitica infection. We hypothesize that IL-6 may be a crucial regulator of inflammatory responses to infection by influencing the cytokine response of host cells involved in response to Y. enterocolitica infection. We also hypothesize that the IL-6 mediated tempering of inflammatory responses may be triggered by Y. enterocolitica encoded molecules. To test these hypotheses we propose the following specific aims 1) Identify the cells producing IL-6 in response to Y. enterocolitica infection and 2) the cells responding to IL-6 during infection in the Peyer´s patch, mesenteric lymph node, and spleen. These data will give us insight into which host cells are modulating the host response to infection. 3) Test the contribution of the IL-6 modulated cytokines to the immunopathogenesis of intestinal yersiniosis. Mice deficient in IL-6 have distinct cytokine expression profiles and many of these cytokines are critical to the resolution of disease but it is unknown how mis-regulation of these cytokines contributes to pathology. These data will explore the connection between IL-6 mediated modulation of the immune response and Yersinia virulence. Altogether, these data will give us insight into how IL-6 contributes to the pathogenesis of Yersinia infection and how immune pathologies are prevented during self limiting infections. These data may provide insight into the etiology of chronic intestinal inflammation
Keywords: Acute; anakinra; Anti-inflammatory; Anti-Inflammatory Agents; Area; Back; Bacteria; Bacterial Infections; Cells; Child; Chronic; Clinical; Communicable Diseases; Complex; cytokine; Data; Disease; enteric pathogen; Etiology; feeding; Food; Gastrointestinal Diseases; Goals; Immune; Immune response; Immune system; In Vitro; in vivo; Infection; Inflammation; Inflammatory; Inflammatory disease of the intestine; Inflammatory Response; inhibitor/antagonist; insight; Interleukin-1; Interleukin-6; Intestines; Knowledge; Lead; Learning; lymph nodes; Mediating; Mesentery; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mortality Vital Statistics; Mus; oral infection; Pasteurella pseudotuberculosis; pathogen; Pathogenesis; Pathology; Plague; Plasmids; Play; prevent; programs; Regulation; Research Personnel; Resolution; response; Risk; Role; Source; Spleen; Staging; Structure of aggregated lymphoid follicle of small intestine; Syndrome; T cell response; Testing; Type III Secretion System Pathway; Virulence; Virulence Factors; Water; Yersinia; Yersinia enterocolitica; Yersinia infections
Project start date: 2007-06-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-04-119
5R01AI067716-05 (2011): $350940
CABOHYDRATE SYNTHETIC CHEMISTRY
H Peter
Sanford-burnham Medical Research Institcity: La Jolla country: United States (us)
Abstract: Core A will synthesize oligosaccharides derivatives, which are critical for the research projects I, II, and III. The Core is an important part of this program project in that it will provide invaluable oligosaccharides and glycopeptides to determine ligand specificity of carbohydrate-binding proteins and the roles of cell surface oligosaccharides in adhesion. In addition, the Core will provide carbohydrate rhicroarray including heparan sulfate oligosaccharide array for assaying carbohydrate-binding proteins
Keywords: Adhesions; Agonist; Binding (Molecular Function); Biological Assay; carbohydrate binding protein; Carbohydrates; CCL21 gene; Cell surface; Denmark; Development; Employment; Faculty; Funding; Galactose; Glycopeptides; Goals; Heparin; Heparitin Sulfate; Homing; Inorganic Sulfates; Institutes; Knock-out; L-Selectin; Laboratories; Libraries; Ligands; lymph nodes; Lymphocyte; member; neoplastic cell; Normal Cell; novel; Oligosaccharides; Paper; Participant; Peripheral; Polysaccharides; Positioning Attribute; Preparation; Process; Productivity; Program Research Project Grants; programs; Publications; Publishing; Research Project Grants; Resources; Rest; Role; Scientist; sialyl-2-3-(6`-sulfo)galactosyl-1-4-(fucopyranosyl-1-3)-N-acetylglucosamine; Side; Specificity; Staging; sulfation; Switzerland; Synthesis Chemistry; Travel; Unspecified or Sulfate Ion Sulfates; Work
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5P01CA071932-14_9002 (2011): $211893
THE ROLE OF CARDS TOXIN IN GENESIS AND EXACERBATION OF ALLERGIC INFLAMMATION
H Peter
University Of Texas Hlth Sci Ctr San Antcity: San Antonio country: United States (us)
Abstract: Asthma is a chronic disease impacting more than 23 million Americans. The factors leading to asthma are varied but several common and well-established risk factors include genetics, environment, allergen exposure, and infection with atypical bacterial pathogens. Mycoplasma pneumoniae is a common atypical bacterial pathogen strongly associated with wheezing in children and acute exacerbations of asthma in adults. A causal link between any atypical bacterial product and asthma was lacking, until, we identified a M. pneumoniae ADP-ribosylating/vacuolating toxin called Community Acquired Respiratory Distress Syndrome ToXin (CARDS TX) that is present in respiratory secretions of many of our severe refractory asthmatics and patients with acute exacerbations of asthma yet rarely detected in healthy controls. These data strongly suggest that CARDS TX represents a single molecule tightly linked to the pathogenesis of a large subset of asthma cases. We established a mouse model that allows us to investigate the immunological mechanisms responsible for CARDS TX-mediated pulmonary inflammation in both the naive and the atopic lung. Using our model, we demonstrated that naive mice receiving a single exposure to rCARDS TX exhibit an eosinophilic/lymphocytic inflammation leading to an asthma-like phenotype. Further, mice sensitized with OVA albumin or house dust mites and subsequently exposed to CARDS TX develop exacerbated eosinophilic/lymphocytic inflammation and hyperresponsiveness. The Aims for this project are 1) Investigate the immunological basis for the cellular inflammatory response induced by CARDS TX through elucidation of the molecular and cellular components responsible for the CARDS TX-mediated asthma-like responses in naive mice. 2) Investigate the immunological basis for CARDS TX-mediated exacerbation of allergic inflammation. We will determine the cellular and molecular mechanisms responsible for the CARDS TX-mediated exacerbation of allergic inflammation. 3) Investigate the immunological basis for CARDS TX promotion of inflammation using in vitro cell culture models with human cells. We will determine the cellular and molecular mechanisms responsible for the CARDS TX-mediated alteration of T-cell function
Keywords: Acute; Adult; African American; Albumins; Allergens; Allergic; Allergic inflammation; American; Animal Model; Animals; Asthma; asthmatic patient; Bacterial Infections; Bacterial Toxins; base; Biochemical; Cell Culture Techniques; Cell physiology; Cells; Child; Chronic; Chronic Disease; Clinical; Community Acquired Respiratory Distress Syndrome Toxin; Data; Development; Diagnostic; Disease; Environment; Exhibits; Exposure to; Genetic; Goals; Health; Human; Immune system; improved; In Vitro; Infection; Inflammation; Inflammatory Response; insight; Intervention; Knowledge; Link; Lung; Lymphocyte; Mediating; Mediator of activation protein; Mission; Modeling; Molecular; mouse model; Mus; Mycoplasma pneumoniae; Nature; novel; pathogen; Pathogenesis; Pathology; patient population; Phenotype; Pneumonia; Process; Pyroglyphidae; Recombinants; Refractory; respiratory; response; Risk Factors; Role; single molecule; success; T-Lymphocyte; Testing; Tissues; tool; Toxin; translational study; Wheezing; Woman; Work
Relevance: This project is relevant to the NIH´s mission to improve human health because it investigates the molecular mechanisms contributing to the development of asthma due to atypical bacterial infection. This study has the potential to provide insight into the how a bacterial toxin can cause and worsen asthma in humans. Our animal models and translational studies will provide the baseline knowledge and tools to for novel asthma interventions
Project start date: 2011-07-01
Project end date: 2016-06-30
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-AI-10-013
2U19AI070412-06_6699 (2011): $261682
THE ROLE OF HUR IN MUTANT SOD1 DYSREGULATION OF VEGF MRNA PROCESSING
H Peter, Professor
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Grant 5R01NS064133-04 from National Institute Of Neurological Disorders And Stroke
Abstract: Amyotrophic lateral sclerosis (ALS) is a catastrophic degenerative disease of motor neurons that inexorably leads to progressive weakness and death. Genetic depletion of vascular endothelial growth factor (VEGF) leads to selective degeneration of motor neurons, providing a direct link between VEGF and ALS. Furthermore, VEGF attenuates the phenotype of ALS mice expressing the copper-zinc superoxide dismutase (SOD)-1 mutation. Posttranscriptional regulation plays a critical role in VEGF expression, particularly under conditions of cellular stress, allowing an adaptive response to promote cell survival. We recently showed that mutant SOD1 disrupts VEGF posttranscriptional regulation, leading to a significant decline in RNA and protein expression. This finding supports the toxic gain of function hypothesis for SOD1-associated ALS. These initial observations, funded by an exploratory R21 grant and recently published (Lu et al., 2007), have led to three important findings that begin to delineate the mechanism for this toxic effect. First, we discovered that mutant SOD1 is capable of directly binding AU-rich elements (ARE) in the 3´ untranslated region (3´UTR) of VEGF. These cis elements are critical for posttranscriptional regulation of VEGF through interaction with cellular factors. Second, we have found that mutant but not wild-type SOD1 associates with HuR, a major regulator of VEGF mRNA stability via the ARE. Third, mutant SOD1 leads to cytoplasmic translocation and posttranslational modification of HuR. Based on these findings, we hypothesize in this proposal that mutant SOD1 exerts its negative effect on VEGF mRNA processing by disrupting the normal regulatory function of HuR. We propose three specific aims 1) To investigate the novel RNA binding property of mutant SOD1 and its negative effect on HuR. 2) To investigate whether mutant SOD1, through its protein-protein or protein-RNA interaction, disrupts the RNA stabilizing function of HuR, or increases the association of VEGF mRNA with translational silencers or RNA destabilizers. 3) To investigate how mutant SOD1 induces HuR translocation to the cytoplasm and its post-translational modification. The long term objective of this proposal is a) to determine how mutant SOD1 disrupts VEGF posttranscriptional regulation and b) the impact of this novel function on the ALS phenotype. Amyotrophic lateral sclerosis is a relentless disease of motor neurons that leads to progressive paralysis of the muscles and ultimately death. There is no cure for this disease or any mitigating therapy. This proposal will address a novel area of growth factor regulation that may contribute to the cause of this disease, and thus may ultimately lead to novel therapies
Keywords: 3` Untranslated Regions; 5` Untranslated Regions; Abbreviations; Address; Affect; alpha-tocopherol transfer protein; Amino Acid Sequence; Amyotrophic Lateral Sclerosis; Antibodies; Antioxidants; Appearance; Area; Attenuated; base; Be++ element; Beryllium; Binding (Molecular Function); BRF1 gene; butyrate response factor 1; Cell Survival; Cellular Stress; Cessation of life; Clinical; Code; Complex; copper zinc superoxide dismutase; crosslink; Cultured Cells; Cuprozinc Superoxide Dismutase; cyclooxygenase 2; Cytoplasm; Cytoplasmic Granules; Dactinomycin; Degenerative Disorder; Disease; Doxycycline; effective therapy; Electrophoretic Mobility Shift Assay; Elements; Embryo; EMSA; end stage disease; Enzyme-Linked Immunosorbent Assay; Enzymes; Familial Amyotrophic Lateral Sclerosis; Funding; gain of function; Gene Expression; Gene Expression Regulation; Genes; Genetic; genetic regulatory protein; Genetic Transcription; Grant; Growth Factor; Half-Life; Health; IL8 gene; Immunoprecipitation; In Vitro; in vivo; in vivo Model; Indium; Interleukin-8; Interleukins; Investigation; Lead; Ligands; Link; Location; Maintenance; Messenger RNA; Methylation; Modification; Molecular; motor neuron degeneration; Motor Neuron Disease; Motor Neurons; mRNA Expression; mRNA Stability; Mus; Muscle; mutant; Mutant Strains Mice; Mutation; Nature; Neuroblastoma; Neurodegenerative Disorders; novel; nucleocytoplasmic transport; Paralysed; Phenotype; Phosphorylation; Play; Polyribosomes; Post-Translational Protein Processing; preference; Process; Progressive Disease; Property; protein expression; protein protein interaction; Proteins; PTGS2 gene; Publishing; Regulation; response; Ribonucleoproteins; RNA; RNA Binding; RNA Degradation; RNA Processing; RNA Recognition Motif; RNA Splicing; RNA-Binding Proteins; RNA-Protein Interaction; Role; Spinal Cord; Stress; Superoxide Dismutase; superoxide dismutase 1; Symptoms; Tetanus Helper Peptide; Tetracyclines; Time; TIS11 protein; tissue/cell culture; TNF gene; Toxic effect; Transcript; Transgenic Mice; Transgenic Organisms; Translations; Tumor Necrosis Factor-alpha; Ubiquitination; ultraviolet; Untranslated Regions; Vascular Endothelial Growth Factors; Visual; Work
Project start date: 2008-09-30
Project end date: 2012-02-28
Budget start date: 1-MAR-2011
Budget end date: 28-FEB-2012
PFA/PA: PA-07-070
5R01NS064133-04 (2011): $269581
ROLE OF B7-1 IN PODOCYTES IN PATHOGENESIS OF PROTEINURIA
H Peter, Associate Professor Of Medicine
Massachusetts General Hospitalcity: Boston country: United States (us)
Grant 5R01DK062472-10 from National Institute Of Diabetes And Digestive And Kidney Diseases
Keywords: Actins; Adhesions; Affect; Antigen-Presenting Cells; B-Lymphocytes; base; Binding (Molecular Function); Calcineurin; Cathepsin L; CD28 gene; CD80 gene; cell body (neuron); Cell Communication; Cells; Characteristics; clinically significant; Complex; Cyclosporine; Cytoplasmic Tail; Cytoskeleton; Data; DNA Sequence Rearrangement; Down-Regulation; Extracellular Matrix; Filtration; Foot Process; Functional disorder; Gene Delivery; glomerular basement membrane; glomerulosclerosis; Goals; Grant; Health; Human; in vivo; insight; Integral Membrane Protein; Integrins; Intercellular Junctions; Kidney; Kidney Diseases; Knockout Mice; Lead; Left; Link; Lupus Nephritis; Mediating; Microfilaments; Modeling; Molecular; Mus; Mutation; nephrin; novel; Pathogenesis; Pattern; podocyte; Process; protein B; Proteins; Proteinuria; Publishing; Regulation; Reporting; Role; Severities; Signal Pathway; Signal Transduction; slit diaphragm; Structure; synaptopodin; T-Cell Activation; T-Lymphocyte; Testing; Up-Regulation (Physiology); Work
Relevance: PROJECT SUMMARY The work proposed here should provide insight into the molecular mechanism whereby B7-1 expression in podocytes causes proteinuria. This should in the long-term enable us to develop novel, selective podocyte-protective therapies that tackle proteinuria and progression of glomerulosclerosis by blocking the activity of B7-1 in podocytes
Project start date: 2002-07-01
Project end date: 2013-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01DK062472-10 (2011): $377313
7R01DK062472-09 (2010): $226728
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