A genetic and immunological investigation of JAK-STAT in the pathogenesis of Celiac Disease

JAK-STAT 在乳糜泻发病机制中的遗传和免疫学研究

基本信息

批准号：
10191231
负责人：
Xiao-Fei Kong
金额：
$ 16.55万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2021-09-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10191231
关键词：
Affect Agonist Atrophic Autoimmune Diseases Bioinformatics Biological Biological Assay CD4 Positive T Lymphocytes Celiac Disease Cellular biology Chromosome 21 Clinical Clinical Data Cytokine Receptors Cytotoxic T-Lymphocytes Databases Development Development Plans Disease Down Syndrome Drug Targeting Exhibits Gastrointestinal Diseases Gene Dosage Gene Expression Profile General Population Genes Genetic Genetic Determinism Genetic Diseases Genetic Screening Germ Lines Gluten Gluten-free diet Goals HLA-DQ2 HLA-DQ8 antigen Helper-Inducer T-Lymphocyte Human Human Subject Research IFNAR1 gene IFNAR2 gene IFNGR2 gene IL10RB gene Immune Immunity Immunologics Immunology Impairment Individual Inflammatory Inherited Insulin-Dependent Diabetes Mellitus Interferon Receptor Interferon-alpha Interferons Interleukin-15 International Investigation Knowledge Laboratories Lead Libraries Measures Mediating Mentors Molecular Molecular Profiling Mutation Pathogenesis Pathway interactions Patients Pattern Phenocopy Phenotype Physicians Predisposition Production RNA Receptor Gene Reporting Research Research Personnel Risk Role STAT1 gene STAT3 gene Sampling Scientist Serum Severities Signal Transduction T-Cell Development T-Lymphocyte Testing Thyroiditis Time Training Training Programs Transcript Transducers Translational Research Work adaptive immunity base career career development clinical investigation clinical phenotype clinically significant cohort cytokine design exome sequencing gain of function genetic approach genetic risk factor genetic variant high risk indexing inhibitor/antagonist interferon alpha receptor intestinal villi monocyte patient oriented receptor recruit research and development response screening single-cell RNA sequencing skills therapeutic target transcription factor transcriptome sequencing

项目摘要

The proposal details a comprehensive five years training program to expand my skills as a physician-scientist. The research plan is focused on JAK-STAT pathway in Celiac Disease (CeD), but the training plan includes extensive didactics in human subject research, bioinformatics and laboratory-based training on T cell immunology. CeD is an immune mediated gastrointestinal disease that arises in patients with a permissive HLA-DQ2/HLA-DQ8 genetic background. The only available treatment for CeD is to follow a gluten-free diet. Patients with germline gain-of-function (GOF) STAT3 mutations and Down Syndrome have an estimated 40- fold and 5-fold higher risk of CeD, respectively, than the general population, along with a predisposition for other autoimmune diseases, including thyroiditis and Type I Diabetes. Patients with Down Syndrome have three copies of the gene for interferon (IFN) receptors on chromosome 21 and thus constitutive JAK-STAT activation. The central hypothesis is that interferon and cytokines mediated JAK-STAT overactivation may cause loss of T cell tolerance to gluten and an increased risk for CeD. The overall goal of this research is to investigate the mechanism of JAK-STAT activation in the pathogenesis of CeD. To accomplish this, first, we will conduct genetic investigation in 100 index cases with familial CeD and search for genetic variants in the JAK-STAT pathway. We will also expand our cohort of CeD patients with known genetic diseases affecting JAK-STAT activation, include patients with GOF-STAT3 and DS. Second, we will assess the key molecules in the JAK-STAT pathway, including agonists, receptors, STAT and their phosphorylated forms, ISGs in monocyte and CD4+ T cells to identify a molecular signature of active CeD. Third, we will investigate the mechanisms of JAK-STAT overactivation on gluten-specific CD4+ T cells through both single cell RNA-Seq and amplified T cell libraries, followed by testing the functional impact of JAK inhibitors on gluten-specific T cells. The results of this study will delineate JAK-STAT activation and its potential as a therapeutic target for Celiac Disease. Furthermore, through the proposed complementary career development plan, I will gain additional training in clinical investigation on the genetics and immunology of CeD; advanced bioinformatic analysis with RNA-seq; and laboratory-based training in gluten specific CD4+ T cells biology. Throughout this research and career development activities, I will be mentored by a team lead by Dr. Timothy Wang, an internationally recognized physician-scientist and an expert in inflammatory cytokines and their role in human gastrointestinal diseases. I am committed to a career as an independent investigator in patient-oriented translational research; and have designed my training plan to acquire the knowledge and skills needed to make a meaningful and substantial contribution to the field by using a functional genetics approach to discover the therapeutic targets in gastrointestinal diseases.

该提案详细介绍了一项全面的五年培训计划，以扩大我作为医生科学家的技能。该研究计划的重点是乳糜泻（CED）的JAK-Stat途径，但培训计划包括人类学科研究，生物信息学和基于实验室的T细胞培训的广泛教学法免疫学。 CED是一种免疫介导的胃肠道疾病，在允许的患者中产生 HLA-DQ2/HLA-DQ8遗传背景。 CED唯一可用的治疗方法是遵循无麸质饮食。种系功能获得（GOF）STAT3突变和唐氏综合症患者的患者估计有40-- CED的折叠风险分别比一般人群高5倍，以及其他自身免疫性疾病，包括甲状腺炎和I型糖尿病。唐氏综合症患者患有在21染色体上的干扰素（IFN）受体的基因的三副激活。中心假设是干扰素和细胞因子介导的Jak-Stat过度活化可能导致T细胞耐受性丧失对面筋的耐受性，并增加CED的风险。这项研究的总体目标是研究JAK-STAT激活在CED发病机理中的机制。首先，为了实现这一目标，我们将对具有家族性CED的100例指数病例进行遗传研究，并在遗传变异中寻找遗传研究 Jak-Stat Pathway。我们还将扩大患有影响的遗传疾病的CED患者的队列 JAK-STAT激活包括患有GOF-STAT3和DS的患者。其次，我们将评估关键分子 Jak-Stat途径，包括激动剂，受体，Stat及其磷酸化形式，单核细胞和CD4+ T细胞以鉴定活性CED的分子特征。第三，我们将调查通过单细胞RNA-Seq和放大的T细胞文库，然后测试JAK抑制剂对面筋特异性T细胞的功能影响。这项研究的结果将描述Jak-STAT激活及其作为乳糜泻的治疗靶标的潜力疾病。此外，通过拟议的互补职业发展计划，我将获得更多对CED遗传学和免疫学的临床研究培训；高级生物信息学分析与 RNA-seq;以及基于实验室特异性CD4+ T细胞生物学的实验室培训。在整个研究中职业发展活动，由国际上的蒂莫西·王（Timothy Wang）博士领导的团队将指导我公认的医师科学家和炎症细胞因子的专家及其在人类胃肠道中的作用疾病。我致力于从事以患者为导向的转化研究的独立研究者的职业；并设计了我的培训计划，以获取使有意义和有意义的知识和技能通过使用功能遗传学方法来发现治疗靶标，对现场做出了重大贡献在胃肠道疾病中。