STAT3 variants as a rheostat of immune tolerance

STAT3 变体作为免疫耐受的变阻器

基本信息

批准号：
10328097
负责人：
Mark S Anderson
金额：
$ 176.58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-17 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10328097
关键词：
Animal Model Autoantibodies Autoimmune Diabetes Autoimmunity CRISPR/Cas technology Cell model Cells Childhood Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Complex Critical Pathways Defect Diagnosis Disease Epistatic Gene Functional disorder Genetic Engineering Genetic Models Grant Health Human Human Genetics Immune Immune System Diseases Immune Tolerance Immune system Inflammation Insulin-Dependent Diabetes Mellitus Lead Maps Mediating Methods Modeling Mus Mutation Outcome Pathogenesis Patients Personal Satisfaction Phage ImmunoPrecipitation Sequencing Population Process Program Research Project Grants Resources STAT3 gene Sampling Signal Transduction Skin Syndrome T-Lymphocyte Variant Work base central tolerance gain of function gene interaction genetic variant genome editing improved mouse model novel peripheral tolerance programs repaired response synergism therapy development treatment strategy

项目摘要

Project Summary/Abstract (Overall) Dysregulation of the immune system can have severe consequences on health and wellbeing. Although this is often a complex process, recent progress in human genetics has allowed for the identification of single gene variants that are strongly associated with immune dysregulation. Here, in this program project grant three complementary teams will be working together to further unravel how heterozygous mutations that lead to gain of function activity (GOF) of the STAT3 gene can strongly predispose to disease. Moreover, through our efforts we hope to discover potential new methods to reverse this defect. This program project will have three highly collaborative and interactive projects headed by Drs. Megan Cooper, Mark Anderson, and Alex Marson along with two scientific cores. The major themes of the grant are: 1. More refined analysis of the immune cell dysfunction in STAT3 GOF patients 2. Using state of the art animal modeling approaches to interrogate STAT3 GOF mutations in triggering skin inflammation and type 1 diabetes 3. Utilizing state of the art CRISPR/Cas9 methods to interrogate STAT3 GOF dysfunction 4. Modeling methods to genetically repair defective STAT3 in human cells The long-term objectives of this work are to improve our understanding of how STAT3 can serve as a tunable rheostat to control immune tolerance and immune dysregulation. Results of these studies will help further refine our understanding of autoimmunity inflammation and help improve methods for its treatment and diagnosis.

项目摘要/摘要（总体）免疫系统失调会对健康和福祉产生严重后果。虽然这是通常是一个复杂的过程，人类遗传学的最新进展已经允许识别单个基因与免疫失调密切相关的变异。在这里，在这个计划项目中授予三个互补团队将共同努力，进一步揭示杂合突变如何导致增益 STAT3 基因功能活性的降低 (GOF) 极易诱发疾病。而且，通过我们的努力我们希望发现潜在的新方法来扭转这一缺陷。该计划项目将具有三个高度由博士领导的协作和互动项目。梅根·库珀、马克·安德森和亚历克斯·马森以及两个科学核心。赠款的主要主题是： 1. STAT3 GOF患者免疫细胞功能障碍的更精细分析 2. 使用最先进的动物建模方法来询问 STAT3 GOF 突变的触发皮肤炎症和 1 型糖尿病 3. 利用最先进的 CRISPR/Cas9 方法来检测 STAT3 GOF 功能障碍 4. 基因修复人类细胞中缺陷STAT3的建模方法这项工作的长期目标是提高我们对 STAT3 如何作为可调变阻器控制免疫耐受和免疫失调。这些研究结果将有助于进一步加深我们对自身免疫性炎症的理解，并帮助改进其治疗方法和诊断。