The role of GLUT3 in the genetics of autoimmunity and immunometabolism

GLUT3 在自身免疫和免疫代谢遗传学中的作用

基本信息

批准号：
10240294
负责人：
Kim R Simpfendorfer
金额：
$ 12.77万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10240294
关键词：
Achievement Adult Advisory Committees Affect Animal Model Antibodies Arthritis Autoimmune Diseases Autoimmunity Biological Assay Biological Response Modifier Therapy Bone Marrow CD4 Positive T Lymphocytes Carrier Proteins Cell Lineage Cell physiology Cells Chromosome 12 Collagen Arthritis Collagen Type II Copy Number Polymorphism Development Development Plans Diamond Disease Environment Equipment Faculty Family member Foundations Future Gene Deletion Gene Dosage Genes Genetic Genotype Glucose Transporter Glycolysis Glycolysis Inhibition Goals Helper-Inducer T-Lymphocyte Hematopoietic Human Human Resources Immune Immune response Immune system Immunization Immunophenotyping Inflammatory Institutes K-Series Research Career Programs Knockout Mice Knowledge Leadership Literature Malignant Neoplasms Measures Mediator of activation protein Medical Research Mentors Mentorship Metabolic Metabolism Modeling Mus Myeloid Cells Pathogenesis Pathogenicity Peripheral Blood Mononuclear Cell Phase Phenotype Play Polyarthritides Population Predisposition Registries Regulation Regulatory T-Lymphocyte Research Research Proposals Resources Rheumatoid Arthritis Risk Role SLC2A1 gene Serum Severities Son System Systems Development T-Cell Activation T-Cell Proliferation T-Lymphocyte Techniques Testing The Sun Therapeutic Training Validation autoimmune arthritis career development cell type collagen antibody induced arthritis conditional knockout design disability drug discovery effector T cell genetic variant glucose transport human subject immune system function improved lymphocyte proliferation mortality mouse development mouse model patient subsets polarized cell prevent protective effect research and development targeted treatment therapeutic candidate therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT Rheumatoid arthritis (RA) is the most common adult form of inflammatory polyarthritis and is associated with substantial disability and increased mortality. Current biologic therapies are effective in a subset of patients, but there is a clear need for improved therapeutic approaches. Deletion of the SLC2A3 gene (encoding the GLUT3 glucose transporter protein) on chromosome 12 is strongly protective for RA in humans. In order to harness the protective effect of this genetic variant for use in developing preventative or therapeutic measures for RA, it is crucial to understand the cell types, cell functions and disease pathogenic mechanisms altered by SLC2A3 haploinsufficiency. The reduced risk for RA in deletion-carriers suggests that corresponding reduced expression of GLUT3 in cells dependent on GLUT3 for their function reduces risk for RA development; we have shown reduced expression in both T cells and myeloid cell types of deletion-carriers. As CD4 T cells are considered to be a key driver in the initiation of RA, and recent literature indicate that GLUT3 is required for normal T cell proliferation, our primary hypothesis is that the arthritis protective mechanism is T cell dependent. The specific aims are to: 1) elucidate the role of Glut3 haploinsufficiency on the development of mouse models of RA, 2) study the requirement for Glut3 sufficiency in CD4+ T cell functions in Slc2a3 conditional knockout mice 3) identify the cell-type intrinsic mechanism of the protective effect of Slc2a3 hemizygosity, and 4) determine requirement of GLUT3 sufficiency for human CD4+ T cell functions and RA-like phenotypes. The above abstract constitutes the revised research proposal component of a K01 career development award application of Dr. Kim Simpfendorfer. Together with the career development plan, this proposal is designed to allow Dr. Simpfendorfer the support and foundation to investigate the validity of GLUT3 as a therapeutic target in RA. Specifically, Dr. Simpfendorfer will receive training and mentorship in research management, leadership and animal models of RA as well as further training in autoimmune disease pathogenesis in mouse and human systems. The achievement of these goals will be accomplished through the mentorship from Dr. Peter K Gregersen, and input from the advisory committee of Drs. Betty Diamond, Laurence Morel, Sun Jung Kim and Yong Rui Zou. Additionally, Kim will receive technical training in animal models of arthritis from Drs. Max Brenner, Anne Davidson and Myoungsun Son. The Feinstein Institute for Medical Research is an ideal institutional environment for Dr. Simpfendorfer's research and career development due to training and mentoring resources, unique human resources such as the Genotype and Phenotype Registry, and the cross- disciplinary expertise of the proposed mentor, advisory committee and institutional faculty. Furthermore, the Feinstein Institute is adequately equipped with the required facilities and equipment to enable productive progress of the described research proposal.

项目摘要/摘要类风湿关节炎（RA）是最常见的成年炎症性多重关节炎，与大量残疾和死亡率增加。当前的生物疗法在一部分患者中有效，但是，显然需要改善治疗方法。删除SLC2A3基因（编码 Glut3葡萄糖转运蛋白）在12号染色体上对人类的RA具有强烈的保护。为了利用这种遗传变异的保护作用，用于制定预防或治疗措施对于RA，了解细胞类型，细胞功能和疾病的致病机制至关重要 SLC2A3单倍宽度。删除载体中RA的风险降低表明相应减少 glut3在细胞中的表达取决于GLUT3的功能可降低RA发育的风险；我们在T细胞和髓样细胞类型的缺失载体类型中的表达降低。因为CD4 T细胞是被认为是RA启动的关键驱动力，最近的文献表明GLUT3是必需的正常T细胞增殖，我们的主要假设是关节炎保护机制取决于T细胞。具体目的是：1）阐明GLUT3单倍性在小鼠模型开发中的作用 2）研究CD4+ T细胞功能的GLUT3足够的需求SLC2A3条件敲除小鼠3）确定SLC2A3半合子的保护作用的细胞类型的固有机制，4）确定GLUT3对人CD4+ T细胞功能和RA样表型的需求。上述摘要构成了K01职业发展奖的修订研究建议部分 Kim Simpfendorfer博士的应用。与职业发展计划一起，该建议旨在允许Simpfendorfer博士的支持和基础研究GLUT3作为治疗靶点的有效性在RA。具体来说，Simpfendorfer博士将接受研究管理的培训和指导，领导 RA的动物模型以及小鼠和人类自身免疫性疾病发病机理的进一步训练系统。这些目标的实现将通过彼得·K博士的指导来实现格雷格森（Gregersen）和博士咨询委员会的意见。贝蒂·戴蒙德（Betty Diamond），劳伦斯·莫雷尔（Laurence Morel Yong Rui Zou。此外，Kim将接受DRS的关节炎动物模型的技术培训。最大限度布伦纳，安妮·戴维森和Myoungsun儿子。费恩斯坦医学研究所是理想的 Simpfendorfer博士的研究和职业发展，由于培训和指导资源，独特的人力资源，例如基因型和表型注册表以及交叉拟议导师，咨询委员会和机构教师的纪律专业知识。此外， Feinstein Institute已配备了所需的设施和设备，以实现生产力所描述的研究建议的进展。