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 这个项目是一个小的赠款计划R 03申请博士埃里克Allenspach，助理教授在 华盛顿大学（UW）儿科。他是NIH指导临床的接受者 科学家研究职业发展奖（K 08）从NIDDK，目前在第四年。博士 Allenspach是儿科流变学和免疫学部门的主治医师， 在儿科自身免疫性疾病的治疗中的临床和研究兴趣。艾伦斯帕奇医生说 研究兴趣是了解调节自身免疫的分子机制，包括罕见的变异 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，研究 在动物模型和使用人类样本中，使用基础和 翻译方法 在目前的申请中，Allenspach博士正在申请NIH R 03基金，以支持一个新的研究领域。 与他的K 08有关，但又不同。Allenspach博士建议研究一种已确定的自身免疫性疾病的生物学作用。 衔接蛋白SH 2B 3中的风险变体对1型糖尿病（T1 D）小鼠模型中T细胞功能的影响。 在SH 2B 3基因中的遗传等位基因（rs3184504）与T1 D之间发现了强关联。在这 我们利用小鼠模型来了解SH 2B 3功能降低如何影响T细胞。K08 该提案集中在SH 2B 3在塑造骨髓发育，功能和抗原呈递中的作用， 与T1 D有关现在，我们小组的初步数据已经确定了SH 2B 3在T细胞中的明确内在作用。 调节IL-2受体途径。在遗传风险等位基因之间发现了一个很强的关联， （rs3184504*T）和T1 D，该等位基因编码亚型SH 2B 3蛋白。Sh 2b 3缺乏， 鼠CD 8 T细胞使它们在体内耐受机制难治，如在鼠CD 8 T细胞中所证实的。 糖尿病模型驱动这种自身免疫的机制尚不清楚。 在这项提案中，我们将测试SH 2B 3的缺陷是否会改变TCR信号转导所需的阈值。 增殖和分化。我们将利用一个完善的小鼠TCR-转基因模型， 与TCR信号报告基因进行体外和体内测试。我们将探讨SH 2B 3是否调节所有的 常见的γ链受体以及这种信号传导如何与TCR信号传导交叉。我们还将测试 SH 2B 3缺陷是否倾向于末端效应记忆细胞，这是一种已知的致病表型， CD 8细胞与T1 D进展相关。这些基础研究将有助于告知机械 这项研究旨在了解SH 2B 3遗传风险变异在促进糖尿病方面的作用，并可以指导未来的人类研究。它 预计这些研究将提供所需的出版物和初步数据， 独立的研究方向，并在职业发展的支持年底申请R 01资助。