Small Molecules Targeting Allele Specific MHC Class II Presentation

针对等位基因特异性 MHC II 类的小分子演示

基本信息

批准号：
8353949
负责人：
AARON W MICHELS
金额：
$ 15.24万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8353949
关键词：
Alleles Autoantigens Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity B-insulin Beta Cell Binding Biological Assay Blood Glucose CD4 Positive T Lymphocytes Celiac Disease Cells Clinical Computer Simulation Diabetes Mellitus Diabetes prevention Disease Docking Effectiveness Ensure Eye diseases Follow-Up Studies Funding Gliadin Goals Grant Heart Diseases Histocompatibility Histocompatibility Antigens Class II Human Immune Immune system Immunologics Immunotherapy In Vitro Inbred NOD Mice Incidence Insulin Insulin-Dependent Diabetes Mellitus Interleukin-10 K-Series Research Career Programs Kidney Diseases Knowledge Lead Leukocytes Major Histocompatibility Complex Mentors Molecular Mus Nerve Pancreas Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacologic Substance Physicians Predisposition Process Production Receptor Signaling Research Research Personnel Research Project Grants Risk Scientist Specificity Structure T cell response T-Cell Receptor T-Lymphocyte Testing Time To autoantigen Transgenic Mice Treatment Efficacy United States National Institutes of Health base career clinical care cytokine deamidation effective therapy immunoregulation improved in vitro testing in vivo islet mouse model novel pre-clinical prevent programs response small molecule small molecule libraries

项目摘要

DESCRIPTION (provided by applicant): A mentored clinical scientist career development award will enable me to continue developing as a physician scientist and become an independent investigator. I have the institutional support and protected time to develop my research career. I have identified two outstanding mentors for my career development award in George Eisenbarth and John Kappler. The goal of the proposed research project is to understand the immunologic mechanisms by which 'drug- like' small molecules can be used to block the underlying autoimmunity in major histocompatibility complex (MHC) class II restricted autoimmune diseases. The human MHC class II molecules DQ8 and DQ2 are the major determinants of both type 1 diabetes and celiac disease with more than 99% of patients with celiac disease having DQ8 or DQ2 and more than 90% of patients with type 1 diabetes have these alleles. By targeting MHC class II molecules, it is possible to use small molecules to block the presentation of autoantigens to T cells while other molecules can stimulate the production of protective cytokines (e.g. IL10). The first two aims of the proposal will evaluate compounds in the NOD mouse which is a spontaneous mouse model for autoimmune diabetes to understand how small molecules alter the presentation of autoantigens to CD4 T cells. Studies will be performed to both prevent and reverse diabetes onset. Follow up studies will be done to ensure the potential therapies are safe and do not abrogate normal immune system function. The final aim looks to evaluate small molecules targeted to the human MHC class II molecule DQ8. Initially in vitro studies will be done to evaluate small molecule response to CD4 T cells restricted to insulin (type 1 diabetes) and gliadin peptides (celiac disease) presented by DQ8. Those small molecules showing specificity and effectiveness in our initial assays will be tested using humanized transgenic mice that contain the DQ8 allele. If successful this proposal will lead to a proof of principle that small molecules targeted to human MHC class II molecules are capable of stimulating and inhibiting CD4 T cell responses to autoantigens and could potentially lead to a safe and specific class of immunotherapy. My overall career goal is to become an independent NIH-funded investigator applying the knowledge gained during my career development award period to better understand the underlying autoimmunity of MHC class II restricted autoimmune disorders and ultimately improve the clinical care for patients afflicted with these diseases. PUBLIC HEALTH RELEVANCE: Type 1 diabetes is an autoimmune disease that results from the body's immune system destroying insulin producing cells and the incidence has dramatically increased over the last two decades. The treatment of diabetes is lifelong insulin administration, and patients with diabetes are at risk for developing complications (eye disease, kidney disease, nerve damage, and heart disease) and low blood sugars. Safe and effective therapies that prevent the body's white blood cells from destroying insulin producing cells in the pancreas are needed, and our research seeks to understand how novel 'drug like' molecules can be used to treat and prevent type 1 diabetes and other related autoimmune diseases.

描述（由申请人提供）：指导的临床科学家职业发展奖将使我能够继续作为医师科学家发展并成为独立研究员。我有机构的支持和受保护的时间来发展我的研究职业。我在乔治·艾森巴斯（George Eisenbarth）和约翰·卡普勒（John Kappler）的职业发展奖中确定了两位杰出的导师。拟议的研究项目的目的是了解可以使用“类似药物”的小分子来阻止主要组织相容性复合物（MHC）II级限制的自身免疫性疾病的基础自身免疫的免疫机制。人类MHC II类分子DQ8和DQ2是1型糖尿病和腹腔疾病的主要决定因素，其中99％以上患有DQ8或DQ2的腹腔疾病患者，1型糖尿病患者中有90％以上具有这些等位基因。通过靶向MHC II类分子，可以使用小分子阻断自身抗原向T细胞的呈递，而其他分子可以刺激保护性细胞因子的产生（例如IL10）。该提案的前两个目标将评估NOD小鼠中的化合物，该化合物是自身免疫性糖尿病的自发小鼠模型，以了解小分子如何改变自身抗原对CD4 T细胞的呈现。将进行研究以预防和反向糖尿病发作。将进行后续研究，以确保潜在的疗法是安全的，并且不会消除正常的免疫系统功能。最终目的旨在评估针对人MHC II类分子DQ8的小分子。最初，将进行体外研究，以评估限制在胰岛素（1型糖尿病）和DQ8呈现的麦芽辛肽（乳糜泻）的小分子反应。那些在我们初始测定中表现出特异性和有效性的小分子将使用包含DQ8等位基因的人源性转基因小鼠进行测试。如果成功，该建议将导致原理证明，靶向人类MHC II类分子的小分子能够刺激和抑制CD4 T细胞对自身抗原的反应，并有可能导致安全和特定的免疫疗法类。我的整体职业目标是成为一名独立的NIH资助的调查员，运用我职业发展奖中获得的知识，以更好地了解MHC II级限制自身免疫性疾病的基本自身免疫性，并最终改善患有这些疾病患者的临床护理。公共卫生相关性：1型糖尿病是一种自身免疫性疾病，它是由于人体的免疫系统破坏了胰岛素产生的细胞，并且在过去的二十年中的发生率显着增加。糖尿病的治疗是终身胰岛素给药，糖尿病患者有发育并发症的风险（眼病，肾脏疾病，神经损伤和心脏病）和低血糖。需要安全有效的疗法，以防止人体的白细胞在胰腺中破坏胰岛素产生细胞，我们的研究试图了解如何使用新颖的“药物（如”分子来治疗和预防1型糖尿病和其他相关的自身免疫性疾病。