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Control of Colitogenic Th17 cells by Vitamin D Receptor Signaling

通过维生素 D 受体信号传导控制致结肠炎 Th17 细胞

基本信息

批准号：
10155045
负责人：
Blake Frey
金额：
$ 3.93万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155045
关键词：
Affect Attention Binding Binding Sites Bioinformatics CD4 Positive T Lymphocytes Calcium Cells Cholesterol Clinic Clinical Clinical Trials Colitis Competence DNA Binding Data Development Disease Enhancers Environmental Risk Factor Feedback Foundations Gene Targeting Genes Genetic Transcription Genome Genomics Goals Health Heterogeneity Homeostasis Hormones IL17 gene IL6 gene IRF4 gene Immune Immune Tolerance Immunogenetics Impairment Incidence Industrialization Inflammation Inflammatory Bowel Diseases Interleukin-10 Interleukin-17 Interleukins Intestines Kinetics Life Style Ligand Binding Ligand Binding Domain Ligands Link Mediating Mentors Molecular Mucous Membrane Mus Nuclear Receptors Oral Orphan Pathogenesis Pathogenicity Pathway interactions Patient Care Patients Physicians Play Population Predisposition Process Production RXR Receptor Signaling Regulator Genes Reporter Reporting Research Role STAT3 gene Scientist Signal Transduction Site Societies Solar Energy Source Specific qualifier value T cell response T-Lymphocyte Techniques Testing Therapeutic Training Transgenic Model Ultraviolet B Radiation Vitamin D Vitamin D Deficiency Vitamin D3 Receptor adaptive immunity base bone health career clinically relevant conditional knockout cytokine dietary differential expression disorder risk experience gastrointestinal genome wide association study genome-wide analysis genomic locus global health immune function improved insight mouse model novel prevent receptor receptor binding receptor expression recruit response responsible research conduct skills small molecule inhibitor training opportunity transcription factor

项目摘要

PROJECT SUMMARY Vitamin D (Vit D) deficiency is estimated to affect over 1 billion people worldwide and is now considered a global health crisis. In addition to maintaining calcium homeostasis and bone health, Vit D plays an important role in regulating adaptive immunity. Low Vit D levels correlate with various immune-mediated diseases, including inflammatory bowel disease (IBD), while Vit D signaling through the vitamin D receptor (VDR) has been linked to immune tolerance. Central to IBD pathogenesis is the dysregulation of proinflammatory Th17 cells, a subset of CD4 T cells that are characterized by their production of interleukin-17A (IL-17A). While these cells normally contribute to homeostasis at mucosal barrier sites, Th17 cells are pathogenic in IBD. We have shown that VDR is upregulated during Th17 differentiation and treatment with Vit D inhibits Th17 production of proinflammatory cytokines (e.g., IL-17A) in favor of the immunosuppressive cytokine, interleukin-10 (IL-10). How Vit D treatment modulates the Th17 response is unclear. To define its mechanism of action, we have generated two complementary murine models that have VDR reporter activity and are conditional knockouts for the VDR ligand binding domain (LBD). Based on our preliminary data, we propose that VDR signaling directly antagonizes activity of the central transcription factor of Th17 cells, RORgt, to negatively regulate Th17 development and function—thereby modulating colitis pathogenicity. In this proposal, we will use our novel transgenic models to determine whether there is heterogeneity of VDR expression within Th17 populations and whether ligand binding by VDR is essential for its actions in limiting Th17 pathogenicity in colitis. Improving our understanding of how this pathway can modulate Th17 function to protect against immune-mediated diseases, such as IBD, will have broad-reaching implications on patient intestinal health and therapy. The proposed training plan for Blake Frey is sponsored by his mentor, Dr. Casey Weaver. The overall goal of the training plan is to provide the PI with a strong foundation for a successful career as a physician-scientist. A project that is clinically relevant, while focused on a fundamental mechanism of disease pathogenesis, represents the ideal training opportunity for an aspiring physician-scientist. As molecular information becomes more integral to patient care, the ability to understand and interpret these types of data will be essential. Providing Blake with the skills to understand the clinical influence of environmental factors on gastrointestinal immune function will enable him to expand our understanding and application of molecular processes to further understand disease and personalize patient therapy. Included in the training plan are experiences that will help the PI: 1) gain competence in a variety of techniques that integrate immunogenetics and bioinformatics; 2) develop hypothesis-driven research; 3) present data in an oral and written format; 4) effectively integrate research and the clinic; 5) collaborate with other scientists; and 6) responsibly conduct research.

项目总结