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NIH指导的临床科学家研究职业发展奖（K08）博士的申请。 埃里克·艾伦斯帕赫（Eric Allenspach），大学儿科学系的代理助理教授 华盛顿（UW）。 Allenspach博士已经完成了他在儿科风湿病学和 免疫学，并且对小儿自身免疫性疾病的治疗具有临床和研究兴趣。 Allenspach博士的具体研究兴趣是了解遗传危险因素在调节 髓样谱系以及先天和适应性免疫反应之间的相互作用。他的长期职业 目标是将自己确立为一个独立资助的原则研究者，研究这些机制 使用基础科学和翻译方法直接在原代人类细胞中。 为了实现这一目标，Allenspach博士正在要求NIH K08支持其他培训和 在以下特定领域中的指导：（1）评估鼠髓毛体和EX的技​​术技能 体内操纵人髓样细胞； （2）与基因敲低和 基因编辑； （3）蛋白质组学方法和大数据分析的其他培训； （4）点头鼠建模 自发糖尿病。 （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； （6）授予技巧和实验室管理 专注于发展独立的研究重点，以转变为科学独立性。 在本应用中，Allenspach博士提出了研究已鉴定自动免疫风险的生物学作用 适配器蛋白SH2B3的变体在1型糖尿病（T1D）的发展和调节中 骨髓。在SH2B3基因中的遗传等位基因（RS3184504）之间发现了牢固的关联 和T1D。在此提案中，我们利用鼠建模来了解降低的SH2B3功能如何影响 T1D开发和在环境压力下的APC。该项目的总体目标是测试 SH2B3风险变体是否改变T1D发病机理。这些研究将侧重于以下领域： AIM 1，我们测试执行SH2B3 T1D风险等位基因会改变髓样APC的固有功能。作为单核细胞 是几个髓样效应细胞的前体，我们在AIM 2中测试是否具有更多前体 炎症过程中的单核细胞导致后代数量增加，包括单核细胞衍生的DC。在 AIM 3，我们直接询问在小鼠中建模的RS3184504*T等位基因是否通过引入T1D贡献 点头小鼠背景上的遗传变化。在此提案中，我们将直接评估 T1D中的这种常见风险变体，并同时获得有关单核细胞生物学的新知识 发病。预计这些研究将提供出版物和初步数据 建立独立的研究方向并在职业发展结束时申请R01资金 支持。