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

• 批准号: 8662772
• 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
• 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/8662772
• 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

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.

描述（由申请人提供）：一个指导临床科学家职业发展奖将使我能够继续发展作为一个医生科学家，并成为一个独立的研究者。我有机构的支持和保护时间来发展我的研究事业。我已经为我的职业发展奖确定了两位杰出的导师，他们是乔治·艾森巴特和约翰·卡普勒。拟议的研究项目的目标是了解免疫机制，通过这种免疫机制，“药物样”小分子可用于阻断主要组织相容性复合体（MHC）II类限制性自身免疫性疾病中的潜在自身免疫。人MHC II类分子DQ 8和DQ 2是1型糖尿病和乳糜泻的主要决定因素，超过99%的乳糜泻患者具有DQ 8或DQ 2，超过90%的1型糖尿病患者具有这些等位基因。通过靶向MHC II类分子，可以使用小分子来阻断自身抗原向T细胞的呈递，而其他分子可以刺激保护性细胞因子（例如IL 10）的产生。该提案的前两个目标将评估NOD小鼠中的化合物，NOD小鼠是一种自发的自身免疫性糖尿病小鼠模型，以了解小分子如何改变自身抗原向CD4 T细胞的呈递。将进行研究以预防和逆转糖尿病发作。将进行后续研究，以确保潜在的治疗是安全的，不会消除正常的免疫系统功能。最终目的是评估靶向人类MHC II类分子DQ8的小分子。最初将进行体外研究以评价对局限于由DQ 8呈递的胰岛素（1型糖尿病）和麦胶蛋白肽（乳糜泻）的CD4 T细胞的小分子应答。在我们的初始测定中显示特异性和有效性的那些小分子将使用含有DQ 8等位基因的人源化转基因小鼠进行测试。如果成功的话，这一提议将导致一个原则的证明，即靶向人类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，并可能导致一种安全和特异性的免疫疗法。我的总体职业目标是成为一名独立的NIH资助的研究人员，应用我在职业发展奖期间获得的知识，更好地了解MHC II类限制性自身免疫性疾病的潜在自身免疫性，并最终改善患有这些疾病的患者的临床护理。