The Role of the Adaptor Protein SH2B3 in Type 1 Diabetes

接头蛋白 SH2B3 在 1 型糖尿病中的作用

• 批准号: 10241937
• 负责人: Eric J Allenspach
• 金额: $ 16.2万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241937
• 关键词: Acute; Adaptor Signaling Protein; Adoptive Transfer; Affect; Alleles; Animal Model; Animals; Antibodies; Antigen Presentation; Area; Autoimmune; Autoimmune Diseases; Basic Science; Beta Cell; Big Data; Biological; Biological Assay; Biology; CD4 Positive T Lymphocytes; Cell Line; Cells; Childhood; Clinical; Clinical Research; Complex; Cytokine Receptors; Data; Data Analyses; Dendritic Cells; Development; Diabetes Mellitus; Disease; Early Intervention; Effector Cell; Environmental Risk Factor; Etiology; European; Event; Exhibits; Exocrine pancreas; Funding; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genotype; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Homologous Gene; Human; Human Genetics; ITGAM gene; ITGAX gene; Immune; Immune response; Immunology; Inbred NOD Mice; Individual; Inflammation; Inflammatory; Innate Immune System; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; K-Series Research Career Programs; Knock-in; Knowledge; Laboratories; Lead; Lymphocyte; Mass Spectrum Analysis; Measures; Mentors; Mentorship; Methods; Modeling; Monocytosis; Mononuclear; Mus; Mutation; Myelogenous; Myeloid Cells; Myelopoiesis; Pathogenicity; Pathway interactions; Peripheral; Phase; Phenotype; Population; Prediabetes syndrome; Production; Proteins; Proteomics; Publications; Receptor Signaling; Relapse; Research; Research Personnel; Rheumatology; Risk; Role; Sampling; Scientist; Sepsis; Severities; Shapes; Signal Transduction; Site; Stress; Susceptibility Gene; Technical Expertise; Techniques; Testing; Tissues; Training; United States National Institutes of Health; Universities; Variant; Virus Diseases; Washington; Work; adaptive immune response; adaptive immunity; base; career; career development; cytokine; diabetes pathogenesis; diabetes risk; disorder risk; embryonic stem cell; genetic risk factor; genomic locus; high risk; human subject; in vivo; insulin dependent diabetes mellitus onset; interest; islet; knock-down; lymph nodes; macrophage; monocyte; mortality; mouse model; novel; pediatric department; professor; progenitor; protective effect; recruit; repository; risk variant; symposium; trait; translational approach

PROJECT SUMMARY/ABSTRACT: This project is a NIH Mentored Clinical Scientist Research Career Development Award (K08) application for Dr. Eric Allenspach, an Acting Assistant Professor in the Department of Pediatrics at the University of Washington (UW). Dr. Allenspach has completed his clinical training in Pediatric Rheumatology and Immunology and has both a clinical and research interest in the treatment of pediatric autoimmune conditions. Dr. Allenspach's specific research interest is understanding the role of genetic risk factors in regulating the myeloid lineage and the interaction between the innate and adaptive immune responses. His long-term career goal is to establish himself as an independently-funded principle investigator studying these mechanisms in both animal models and directly in primary human cells using basic science and translational approaches. In order to achieve this goal, Dr. Allenspach is requesting the NIH K08 support for additional training and mentorship in the following specific areas: (1) assessment of murine myelopoiesis and technical skills in ex vivo manipulating human myeloid cells; (2) training in laboratory techniques related to gene knockdown and gene editing; (3) additional training in proteomic approaches and big data analysis; (4) NOD murine modeling of spontaneous diabetes. (5) presenting at scientific conferences, career development seminars, and additional classroom-based training relevant to this project; and (6) grantsmanship and laboratory management with a focus on developing an independent research focus with a goal of transitioning to scientific independence. In the present application, Dr. Allenspach proposes studying the biologic role of an identified autoimmune risk variant in the adaptor protein SH2B3 on the development of type 1 diabetes (T1D) and in regulating myelopoiesis. 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 APCs during T1D development and under environmental stress. The overall goal of the project is to test whether the SH2B3 risk variant alters T1D pathogenesis. These studies will focus on the following areas: In Aim 1, we test does the SH2B3 T1D risk allele alter the inherent function of the myeloid APCs. As monocytes are the precursors to several myeloid effector cells, we test in Aim 2 whether having more precursor monocytes during inflammation lead to increased numbers of progeny including monocyte-derived DCs. In Aim 3, we ask directly whether the rs3184504*T allele modeled in mice contributes to T1D by introducing the genetic change on the NOD mouse background. In this proposal, we will directly assess the functional role for this common risk variant in T1D, and, in parallel, gain new knowledge about monocyte biology relevant to T1D pathogenesis. 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： 该项目是美国国立卫生研究院指导临床科学家研究职业发展奖(K08)的博士申请。 埃里克·阿伦斯帕奇，加州大学儿科系代理助理教授 华盛顿(UW)。Allenspach医生已经完成了他在儿科风湿病和 在治疗儿科自身免疫性疾病方面具有临床和研究兴趣。 Allenspach博士的具体研究兴趣是了解遗传风险因素在调节 髓系谱系以及先天免疫反应和获得性免疫反应之间的相互作用。他长期的职业生涯 目标是将自己确立为研究这些机制的独立资助的主要调查员 既有动物模型，也有利用基础科学和翻译方法直接在原代人类细胞中进行研究的技术。 为了实现这一目标，Allenspach博士正在请求NIH K08支持提供额外的培训和 以下具体领域的指导：(1)评估小鼠的骨髓生成和在实验中的技术技能 活体操作人类髓系细胞；(2)与基因敲除和 基因编辑；(3)蛋白质组学方法和大数据分析方面的额外培训；(4)NOD小鼠模型 自发性糖尿病。(5)在科学会议、职业发展研讨会和其他 与该项目相关的基于课堂的培训；以及(6)资助金和实验室管理 专注于发展独立的研究重点，目标是向科学独立过渡。 在目前的应用中，Allenspach博士建议研究已确定的自身免疫风险的生物学作用 适配蛋白SH2B3变异在1型糖尿病(T1D)发生和调节中的作用 骨髓再生。在SH2B3基因的一个遗传等位基因(Rs3184504)之间发现了很强的关联 和T1D。在这项建议中，我们利用小鼠模型来了解SH2B3功能降低如何影响 在T1D发育和环境胁迫下的APC。该项目的总体目标是测试 SH2B3风险变异体是否改变T1D的发病机制。这些研究将集中在以下方面： 目的1检测SH2B3T1D风险等位基因是否改变髓系APC的固有功能。作为单核细胞 是几个髓系效应细胞的前体，我们在目标2中测试是否有更多的前体 炎症过程中的单核细胞会导致包括单核细胞来源的DC在内的后代数量增加。在……里面 目的3，我们通过引入T1D基因，直接探讨小鼠模型中的rs3184504*T等位基因是否对T1D有贡献。 点头鼠背景上的基因变化。在本提案中，我们将直接评估 这种常见的T1D风险变异，同时获得了与T1D相关的单核细胞生物学的新知识 发病机制。预计这些研究将提供所需的出版物和初步数据 制定独立的研究方向，在职业发展结束时申请R01资金 支持。