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

JAK-STAT 在乳糜泻发病机制中的一般和免疫学研究

基本信息

批准号：
10615604
负责人：
Xiao-Fei Kong
金额：
$ 16.55万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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/10615604
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 Cytotoxic T-Lymphocytes Databases Development Development Plans Disease Down Syndrome 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 Type II Interferon alpha Interferons Interleukin-15 International Investigation Knowledge acquisition Laboratories Lead Libraries Measures Mediating Mentors Molecular Molecular Profiling Mutation Pathogenesis Pathway interactions Patients Pattern Pharmaceutical Preparations Phenocopy Phenotype Phosphorylation Physicians Predisposition Production Proliferating RNA Receptor Gene Reporting Research Research Personnel Risk Role STAT1 gene STAT3 gene Sampling Scientist Serum Severities Signal Transduction Sorting T-Cell Development T-Lymphocyte Testing Thyroiditis Training Training Programs Transcript Transducers Translational Research Work adaptive immunity 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 interleukin-21 intestinal villi monocyte patient oriented permissiveness 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为期五年的综合培训计划，以扩展我作为医师科学家的技能。研究计划重点关注乳糜泻 (CeD) 中的 JAK-STAT 通路，但培训计划包括人类课题研究、生物信息学和 T 细胞实验室培训方面的广泛教学免疫学。 CeD 是一种免疫介导的胃肠道疾病，发生于患有许可性胃肠道疾病的患者中。 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。患有种系功能获得性 (GOF) STAT3 突变和唐氏综合症的患者估计有 40- 患有 CeD 的风险分别比一般人群高 1 倍和 5 倍，并且有以下倾向：其他自身免疫性疾病，包括甲状腺炎和 I 型糖尿病。唐氏综合症患者有 21 号染色体上干扰素 (IFN) 受体基因的三个拷贝，因此构成 JAK-STAT 激活。中心假设是干扰素和细胞因子介导的 JAK-STAT 过度激活可能导致 T 细胞对麸质的耐受性丧失，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 发病机制中的机制。为了实现这一目标，首先我们将对 100 个具有家族性 CeD 的指标病例进行基因调查，并寻找基因变异 JAK-STAT 途径。我们还将扩大患有已知遗传性疾病的 CeD 患者队列 JAK-STAT 激活，包括患有 GOF-STAT3 和 DS 的患者。其次，我们将评估其中的关键分子 JAK-STAT 通路，包括激动剂、受体、STAT 及其磷酸化形式、ISG 单核细胞和 CD4+ T 细胞来识别活性 CeD 的分子特征。第三，我们将调查通过单细胞 RNA-Seq 和 JAK-STAT 对麸质特异性 CD4+ T 细胞过度激活的机制扩增 T 细胞库，然后测试 JAK 抑制剂对麸质特异性 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治疗靶点的潜力疾病。此外，通过拟议的补充职业发展计划，我将获得额外的 CeD 遗传学和免疫学临床研究培训；先进的生物信息分析 RNA测序；以及基于实验室的麸质特异性 CD4+ T 细胞生物学培训。在整个研究过程中和职业发展活动中，我将受到由国际知名人士 Timothy Wang 博士领导的团队的指导。公认的医师科学家和炎症细胞因子及其在人类胃肠道中的作用方面的专家疾病。我致力于作为一名独立研究者从事以患者为导向的转化研究；并设计了我的培训计划，以获得进行有意义且有意义的工作所需的知识和技能通过使用功能遗传学方法发现治疗靶点对该领域做出了重大贡献在胃肠道疾病中。