Investigating the link between REV-ERB and HIF-1a in Th17 cell function

研究 Th17 细胞功能中 REV-ERB 和 HIF-1a 之间的联系

基本信息

批准号：
10721581
负责人：
Kristine Griffett
金额：
$ 7.12万
依托单位：
AUBURN UNIVERSITY AT AUBURN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-11 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10721581
关键词：
Adaptive Immune System Affect African American American Autoimmune Diseases Binding Biological Assay Biological Response Modifier Therapy CD4 Positive T Lymphocytes Cell Differentiation process Cell physiology Cells ChIP-seq Chronic Chronic Disease Colitis Complex Crohn&apos s disease Data Development Disease Drug Targeting EP300 gene Ensure Equilibrium Exons Experimental Autoimmune Encephalomyelitis Feedback Future Gene Targeting Genes Genetic Transcription Genus Hippocampus Glycolysis Health Care Costs Hispanic Human IL17 gene Immune Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Interleukins Knockout Mice Life Ligand Binding Ligands Link Luciferases Mediating Metabolic Metabolic Pathway Microbe Multiple Sclerosis Mus Native Americans Nuclear Receptors Pathogenicity Patients Physiological Play Population Process Promoter Regions Protons Psoriasis Regulation Reporting Repression Reproducibility of Results Research Project Grants Resistance Response Elements Rheumatoid Arthritis Role T cell regulation T-Cell Activation T-Lymphocyte Therapeutic Transcriptional Activation Transcriptional Regulation United States Woman Work Yin autoimmune pathogenesis cancer immunotherapy cost cost effective treatment cytokine drug discovery gene repression graduate student health care availability health disparity insight interest novel novel therapeutics promoter recruit reduce symptoms targeted treatment transcription factor

项目摘要

SUMMARY Autoimmune diseases (i.e., rheumatoid arthritis (RA), Type I Diabetes mellitus (T1DM), multiple sclerosis (MS), Crohn's disease, etc.) affect at least 3% of the US population, although this number appears to be significantly increasing since 2020. Interestingly, many autoimmune diseases occur disproportionately in women. These diseases are chronic, debilitating, and often, life threatening. Recent advances in biologic therapeutics have been successful in reducing symptoms of these chronic diseases in many patients. However, due to the costs associated with these treatments, many Americans still go untreated. In fact, several recent reports have described health disparities in women of Hispanic, African American, and Native American descent, due to availability of healthcare and cost-effective therapies. There is a clear unmet need for lower cost therapeutics for autoimmune diseases. To develop new therapies for autoimmune diseases, we need to further our understanding of the physiological and cellular mechanisms controlling activation and differentiation of Th17 cells. Th17 cells are a subtype of CD4+ lymphocytes that produce the pro-inflammatory cytokine interleukin 17a (IL-17a). Dysregulated activity of Th17 cells is associated with several autoimmune diseases including multiple sclerosis, rheumatoid arthritis, psoriasis, and others. Many of the current biologic therapies target the interleukins produced by Th17 cells to reduce aberrant inflammatory processes. HIF-1 is a transcription factor that plays an important role in the metabolic regulation of Th17 cells. Interestingly, the nuclear receptor REV- ERB, regulates both the Th17 cell activation and differentiation by competing with RORt, and recent work by our lab indicates that REV-ERB may directly repress the expression of HIF-1, providing a “two-hit” mechanism to suppressing T-cell mediated autoimmune diseases. This proposal aims to investigate the role that REV-ERB plays in HIF-1 expression and determine the cellular changes that occur in T-cells during activation with and without the presence of REV-ERB ligands. The data obtained from this work will provide novel insights to the role that REV-ERB plays in T-cell physiology, and provide preliminary data for future drug discovery efforts.

概括自身免疫性疾病（即类风湿关节炎（RA），I型糖尿病（T1DM），多发性硬化症（MS），克罗恩氏病等）至少影响美国人口的3％，尽管这个数字似乎显着自2020年以来的增加。有趣的是，女性的许多自身免疫性疾病发生不成比例。这些疾病是长期的，令人衰弱的，并且经常会威胁生命。生物疗法的最新进展已我们成功地减少了许多患者的这些慢性疾病的症状。但是，由于费用与这些治疗相关，许多美国人仍然没有治疗。实际上，最近有几份报告描述了西班牙裔，非裔美国人和美国原住民血统的健康差异医疗保健和具有成本效益的疗法的可用性。对于较低的成本疗法有明显未满足的需求。用于自身免疫性疾病。为了开发自身免疫性疾病的新疗法，我们需要进一步了解控制TH17激活和分化的物理和细胞机制细胞。 Th17细胞是产生促炎性细胞因子白介素17a的CD4+淋巴细胞的亚型（IL-17A）。 Th17细胞的活性失调与多种自身免疫性疾病有关硬化症，类风湿关节炎，牛皮癣等。当前许多生物疗法的目标 Th17细胞生产的白细胞介素可减少异常的炎症过程。 HIF-1是转录因子这在Th17细胞的代谢调节中起着重要作用。有趣的是，核接收器rev- ERB，通过与RORT竞争以及最近的工作来调节Th17细胞激活和分化我们的实验室表明，Rev-ERB可能直接反映HIF-1的表达，提供了“两击”机制抑制T细胞介导的自身免疫性疾病。该建议旨在调查Rev-erb的作用在HIF-1表达中发挥作用，并确定与和和不存在Rev-ERB配体。从这项工作中获得的数据将为您提供新颖的见解 Rev-erb在T细胞生理学中扮演的角色，并为未来的药物发现工作提供初步数据。