The role of SH2B3 in regulating CD8 T cells in Type 1 Diabetes

SH2B3 在 1 型糖尿病中调节 CD8 T 细胞的作用

• 批准号: 10574346
• 负责人: Eric J Allenspach
• 金额: $ 14.77万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574346
• 关键词: Acceleration; Adaptor Signaling Protein; Adoptive Transfer; Affect; Affinity; Alleles; Animal Model; Animals; Antibodies; Antigen Presentation; Antigen Receptors; Antigens; Area; Autoantigens; Autoimmune; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; Automobile Driving; B-Lymphocytes; Biological; CD8-Positive T-Lymphocytes; CTLA4 gene; Cell Count; Cell Differentiation process; Cell Survival; Cells; Cellular biology; Characteristics; Childhood; Clinical; Coculture Techniques; Code; Complex; Coupled; Cues; Cytokine Receptors; Cytokine Signaling; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Diabetes Mellitus; Disease; Disease Progression; Effector Cell; Environmental Risk Factor; European; Flow Cytometry; Funding; Future; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic study; Genotype; Goals; Grant; Hour; Human; IL2RA gene; IL7 gene; Immune; Immune system; Immunology; Immunophenotyping; In Vitro; Incidence; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interleukin 2 Receptor; Interleukin 2 Receptor Gamma; Interleukin-15; Interleukin-2; K-Series Research Career Programs; Link; Lymphopoiesis; Measures; Memory; Mentors; Mentorship; Modeling; Molecular; Monitor; Mus; Mutation; Myelogenous; Myelopoiesis; National Institute of Diabetes and Digestive and Kidney Diseases; PTPN22 gene; Pancreas; Pathogenicity; Pathway interactions; Peptides; Peripheral; Phenotype; Physicians; Principal Investigator; Proliferating; Proteins; Publications; Receptor Signaling; Refractory; Reporter; Reporting; Research; Rheumatology; Risk; Role; SH2B gene; Sampling; Scientist; Shapes; Signal Transduction; Structure of beta Cell of islet; Surface; Susceptibility Gene; T cell response; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Transgenic Model; United States National Institutes of Health; Universities; Variant; Washington; Western Blotting; Work; autoreactive T cell; career; career development; cell type; cellular targeting; comparison control; cytokine; diabetes risk; disorder risk; exhaust; exhaustion; experience; genetic association; genetic signature; in vitro testing; in vivo; insulitis; interest; interleukin-21; islet; islet autoimmunity; monocyte; mouse model; pediatric department; peptide vaccination; professor; programs; rare variant; receptor; response; risk variant; stem cells; thymocyte; transcription factor; translational approach

PROJECT SUMMARY/ABSTRACT This project is a small grant program R03 application for Dr. Eric Allenspach, an Assistant Professor in the Department of Pediatrics at the University of Washington (UW). He is a recipient of an NIH Mentored Clinical Scientist Research Career Development Award (K08) from the NIDDK and is currently in year four. Dr. Allenspach is an attending physician in both the divisions of Pediatric Rheumatology and Immunology and has a clinical and research interest in the treatment of pediatric autoimmune conditions. Dr. Allenspach’s specific research interest is understanding the molecular mechanisms regulating autoimmunity including rare variants and risk alleles. His long-term career goal is to become an independently funded principal investigator studying genetic mechanisms of autoimmunity in both animal models and using human samples using basic and translational approaches. In the present application, Dr. Allenspach is requesting NIH R03 funding to support a new area of research related, yet distinct, to his K08. Dr. Allenspach proposes studying the biologic role of an identified autoimmune risk variant in the adaptor protein SH2B3 on the function of T cells in mouse models of type 1 diabetes (T1D). A strong association has been found between a genetic allele (rs3184504) in the SH2B3 gene and T1D. In this proposal, we utilize murine modeling to understand how reduced SH2B3 function affects T cells. The K08 proposal focused on the role of SH2B3 in shaping myeloid development, function and antigen presentation as linked to T1D. Now, preliminary data from our group has identified a clear T cell-intrinsic role for SH2B3 in regulating the IL-2 receptor pathway. A strong association has been found between the genetic risk allele (rs3184504*T) and T1D and this allele encodes for a hypomorphic SH2B3 protein. Deficiency of Sh2b3 in murine CD8 T cells renders them refractory to tolerance mechanisms in vivo as demonstrated in a murine diabetes model. The mechanism driving this autoimmunity is not clear. In this proposal, we will test whether deficiency in SH2B3 alters the TCR signaling threshold required for proliferation and differentiation. We will leverage a well-established murine TCR-transgenic models coupled with TCR signaling reporters and test this in vitro and in vivo. We will explore whether SH2B3 regulates all of the common gamma chain receptors and how this signaling intersects with TCR signaling. We will also test whether SH2B3 deficiency skews toward terminal effector memory cells, a known pathogenic phenotype of CD8 cells associated with T1D progression. These basic studies will help inform the mechanistic understanding of the SH2B3 genetic risk variant in promoting diabetes and can guide future human studies. It is anticipated these studies would provide the publications and preliminary data needed to develop an independent research direction and apply for R01 funding at the end of the career development support.

项目摘要/摘要 该项目是针对埃里克·艾伦斯帕赫（Eric Allenspach）博士的小型赠款计划R03申请， 华盛顿大学（UW）的儿科系。他是NIH指导的临床的接受者 科学家研究职业发展奖（K08）来自NIDDK，目前已进入第四年。博士 在小儿风湿病学和免疫学的分区中，艾伦斯帕赫（Allenspach 对小儿自身免疫性疾病治疗的临床和研究兴趣。 Allenspach博士的具体 研究兴趣是了解调查自身免疫性（包括稀有变体）的分子机制 和风险等位基因。他的长期职业目标是成为一名独立资助的首席研究员 在两种动物模型中自身免疫的遗传机制，并使用基本和基本样品使用人类样品 翻译方法。 在本申请中，Allenspach博士要求NIH R03资金支持新的研究领域 与他的K08相关，但与众不同。 Allenspach博士的提案，研究已鉴定自动免疫的生物学作用 适配器蛋白SH2B3中T细胞功能的风险变体在1型糖尿病的小鼠模型中（T1D）的功能。 在SH2B3基因和T1D中的遗传等位基因（RS3184504）之间发现了牢固的关联。在这个 提案，我们利用鼠建模来了解降低的SH2B3功能如何影响T细胞。 K08 提案的重点是SH2B3在塑造髓样发育，功能和抗原表现方面的作用 链接到T1D。现在，我们小组的初步数据已经确定了SH2B3在 调节IL-2受体途径。在遗传风险等位基因之间发现了牢固的关联 （rs3184504*t）和T1D，并且该等位基因编码为型SH2B3蛋白。 SH2B3的不足 鼠CD8 T细胞使它们在鼠类中耐火在体内的耐受性机制 糖尿病模型。驱动这种自身免疫性的机制尚不清楚。 在此提案中，我们将测试SH2B3缺陷是否改变了TCR信号传导阈值 增殖和分化。我们将利用建立完善的鼠TCR转基因模型耦合 使用TCR信号记者，并在体外和体内测试。我们将探索SH2B3是否对所有 常见的伽马链受体以及该信号如何与TCR信号传导相交。我们还将测试 SH2B3缺乏是否偏向终端效应记忆细胞，一种已知的致病表型 与T1D进展相关的CD8细胞。这些基础研究将有助于告知机理 了解促进糖尿病的SH2B3遗传风险变异，并可以指导未来的人类研究。它 预计这些研究将为开发出版物和初步数据提供开发的出版物和初步数据 独立的研究方向并在职业发展支持结束时申请R01资金。