Small Molecules Targeting Allele Specific MHC Class II Presentation

描述（由申请人提供）：指导临床科学家职业发展奖将使我继续发展作为一个内科科学家，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，乔治·艾森巴思和约翰·卡普勒。拟建研究项目的目标是了解在主要组织相容性复合体（MHC） II类限制性自身免疫性疾病中，“药物样”小分子可用于阻断潜在自身免疫的免疫学机制。人类MHC II类分子DQ8和DQ2是1型糖尿病和乳糜泻的主要决定因素超过99%的乳糜泻患者有DQ8或DQ2超过90%的1型糖尿病患者有这些等位基因。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（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。将进行预防和逆转糖尿病发病的研究。后续研究将进行，以确保潜在的治疗是安全的，不会破坏正常的免疫系统功能。最终目的是评估针对人类MHC II类分子DQ8的小分子。最初的体外研究将评估DQ8对胰岛素（1型糖尿病）和麦胶蛋白肽（乳糜泻）限制的CD4 T细胞的小分子反应。这些小分子在我们的初步分析中显示出特异性和有效性，将使用含有DQ8等位基因的人源化转基因小鼠进行测试。如果成功，这一建议将导致一个原则性的证明，即针对人类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资助研究者，运用我在职业发展奖励期间获得的知识，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，并最终改善对这些疾病患者的临床护理。

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.