Analysis of autophagy risk genes in inflammation and tissue homeostasis

项目总结/摘要 人类遗传学的进步现在使该领域能够阐明炎症的病理生理学， 病理学和传染病。虽然免疫介导的组织稳态的机制是 对炎症性疾病和原发性免疫缺陷的遗传分析还不完全清楚， 涉及代表关键免疫检查点的共享蛋白质和途径。绘制基因图谱的努力 炎症性肠病（IBD）的结构已经特别富有成效，导致发现 ATG 16 L1 T300 A，揭示了自噬在先天免疫中的重要性。我们已经证明， ATG 16 L1 T300 A等位基因与环境触发因子共同诱导几种细胞类型特异性 表型导致组织稳态失调和易患炎性病理。因此，在本发明中， 致病性自噬变体的机制表征为以下方面提供了基本见解： 粘膜免疫本申请的重点是了解自噬的遗传扰动 检查点影响粘膜免疫背景下的炎症控制和组织稳态。朝向 为此，我们建议：（1）确定自噬检查点在肠道炎症中的作用，（2）确定自噬检查点在肠道炎症中的作用，（3）确定自噬检查点在肠道炎症中的作用。 自噬控制抗原呈递和组织稳态的分子机制，和（3） 对炎症-自噬联系进行全面的遗传解剖。

PROJECT SUMMARY/ABSTRACT Advancements in human genetics now poise the field to illuminate the pathophysiology of inflammatory pathologies and infectious disease. Although the mechanisms of immune-mediated tissue homeostasis are incompletely understood, genetic analyses of inflammatory disease and primary immunodeficiencies have implicated shared proteins and pathways representing key immune checkpoints. Efforts to map the genetic architecture of inflammatory bowel disease (IBD) have been particularly fruitful, leading to the discovery of ATG16L1 T300A, which revealed the importance of autophagy in innate immunity. We have since shown that the ATG16L1 T300A allele conspires with environmental triggers to induce several cell type-specific phenotypes resulting in tissue dys-homeostasis and predisposition to inflammatory pathology. Thus, mechanistic characterization of a pathogenic autophagy variant has provided fundamental insights into mucosal immunity. The focus of this application is to understand how genetic perturbation of autophagy checkpoints impacts inflammation control and tissue homeostasis in the context of mucosal immunity. Towards this end, we propose to: (1) Define the role of autophagy checkpoints in intestinal inflammation, (2) Identify the molecular mechanisms by which autophagy controls antigen presentation and tissue homeostasis, and (3) Perform a comprehensive genetic dissection of the Inflammation-Autophagy link.