STAT3 variants as a rheostat of immune tolerance

STAT3 变体作为免疫耐受的变阻器

• 批准号: 10576375
• 负责人: Mark S Anderson
• 金额: $ 176.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/10576375
• 关键词: Animal Model; Autoantibodies; Autoimmune Diabetes; Autoimmunity; CRISPR/Cas technology; 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; Heterozygote; Human; Human Genetics; Immune; Immune System Diseases; Immune Tolerance; Immune system; Inflammation; Insulin-Dependent Diabetes Mellitus; 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; 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

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） 免疫系统的失调可能会对健康和福祉产生严重的影响。虽然是 通常是一个复杂的过程，人类遗传学的最新进展允许鉴定单个基因 与免疫失调密切相关的变体。在这里，在这个计划项目中赠款三个 互补的团队将共同努力，进一步揭示如何导致增益的杂合突变 STAT3基因的功能活性（GOF）可以强烈易于疾病。而且，通过我们的努力 我们希望发现潜在的新方法扭转这一缺陷。该计划项目将有三个高度 由DRS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。对STAT3 GOF患者的免疫细胞功能障碍的进一步分析 2。使用艺术状态动物建模方法在触发时询问STAT3 GOF突变 皮肤炎症和1型糖尿病 3。利用最先进的CRISPR/CAS9方法来询问STAT3 GOF功能障碍 4。对人类细胞中基因修复有缺陷的STAT3的建模方法 这项工作的长期目标是提高我们对STAT3如何充当可调节的理解 控制免疫耐受性和免疫失调的风湿病。这些研究的结果将有助于进一步 完善我们对自身免疫性炎症的理解，并帮助改善其治疗方法 诊断。