Elucidating mechanisms of checkpoint inhibitor-induced diabetes

摘要： 本K 08提案将加快主要研究者的进度，以实现其成为 独立的物理学家，科学家，重点是增加我们对免疫机制的理解 检查点抑制剂（CPI）免疫治疗诱导的相关不良事件（irAE），并确定 这些并发症的治疗目标。候选人：Ana Perdigoto博士是耶鲁大学的物理学家， 大学医学院。她完成了内分泌学的临床奖学金和博士后培训， 免疫学。她正在发展免疫内分泌学和免疫学交叉点的专业知识， 通过她对CPI诱导的糖尿病（CPI-DM）机制的研究， 这是在接受针对检查点抑制剂的免疫疗法的癌症患者中出现的。下 Kevan赫罗尔德博士的指导，他是世界著名的内分泌学家和免疫学家，在免疫学方面具有权威性。 1型糖尿病和CPI-DM的免疫学，Perdigoto博士研究了免疫细胞如何修饰胰腺 导致CPI-DM。她将利用培训期间获得的技能，进一步分析 这些irae。职业发展计划：Perdigoto博士将根据 赫罗尔德博士的主要导师她还将得到校内和校外顾问的指导， 在培养独立调查员方面，我们拥有不同领域的专业知识和经验。耶鲁大学 提供了一个协作环境，拥有最先进的设施和资源以及出色的培训 环境和机会。拟议的5年计划建立在Perdigoto博士先前的经验基础上， 进一步丰富了她的培训，提供建立独立性所需的工具，如熟练掌握 生物信息学和基因组数据分析，小鼠遗传学知识，以及富有成效的合作。 研究计划：本提案中涉及的总体前提是免疫细胞和胰岛细胞的相互作用 在组织微环境中，导致CPI-DM的发展（在具体目标1中研究）， 肿瘤可以影响自身免疫，可能是通过呈递共享抗原（在特异性 目标2）。完成这项研究后，Perdigoto博士将能够：1）表征免疫靶点 导致自身免疫的细胞相互作用2）分析新的肿瘤模型， 免疫疗法和肿瘤对自身免疫的影响，以及3）鉴定潜在的治疗靶点以预防不良反应 而不影响肿瘤反应。这一发现将加深我们对 CPI-DM以及CPI治疗引起的其他irAE。完成培训后，博士。 Perdigoto将获得成为独立调查员所需的专业知识， 翻译研究，可以导致诊断或治疗工具的发展，以保护靶细胞 从免疫肿瘤学和潜在自身免疫领域的炎症介质的影响。

Abstract: This K08 proposal will expedite the principal investigator’s progress towards her goal of becoming an independent physician-scientist with a focus on increasing our understanding of mechanisms of immune related adverse events (irAEs) induced by checkpoint inhibitor (CPI) immunotherapies and identifying therapeutic targets of these complications. Candidate: Dr. Ana Perdigoto is a physician-scientist at Yale University School of Medicine. She completed clinical fellowship in Endocrinology and postdoctoral training in Immunology. She is developing an expertise at the crossroads of immuno-endocrinology and immuno- oncology through her work on investigating mechanisms of CPI-induced diabetes (CPI-DM), a complication that arises in cancer patients treated with immunotherapies targeting checkpoint inhibitors. Under the mentorship of Dr. Kevan Herold, a world-renowned Endocrinologist and Immunologist with authority on the immunology of type 1 diabetes and CPI-DM, Dr. Perdigoto investigated how immune cells modify pancreatic islets to cause CPI-DM. She will leverage the skills gained during her training to further analyze mechanisms of these irAEs. Career Development Plan: Dr. Perdigoto will pursue the research in this proposal under the primary mentorship of Dr. Herold. She will also have the guidance of an intramural and extramural advisory team with various areas of expertise and experience in nurturing independent investigators. Yale University provides a collaborative environment with state-of-the-art facilities and resources and excellent training environment and opportunities. The proposed 5-year plan builds on Dr. Perdigoto’s prior experience and further enriches her training to provide the tools needed for establishing independence, such as proficiency in bioinformatics and analysis of genomic data, knowledge in mouse genetics, and productive collaborations. Research Plan: The overall premises addressed in this proposal are that interactions of immune and islet cells in the tissue microenvironment lead to the development of CPI-DM (investigated in Specific Aim 1) and that tumor can impact autoimmunity, potentially through presentation of shared antigens (investigated in Specific Aim 2). Upon completion of the research proposed, Dr. Perdigoto will be able to: 1) characterize immune-target cell interactions that lead to autoimmunity 2) analyze novel tumor models with regards to the impact of immunotherapies and tumor on autoimmunity and 3) identify potential therapeutic targets to prevent adverse events without impacting tumor responses. The findings will enhance our understanding of the pathogenesis of CPI-DM as well as other irAEs arising from CPI treatment. After completing the proposed training, Dr. Perdigoto will have acquired the expertise required to become an independent investigator poised to continue translational studies that can lead to the development of diagnostic or therapeutic tools to protect target cells from the effects of inflammatory mediators both in the field of immuno-oncology and potentially autoimmunity.