Autophagy-mediated defense against inflammation and cancer

项目摘要 来自我们实验室和其他实验室的越来越多的证据表明，溶酶体的一条降解途径，称为 自噬在炎症和癌症生物学中起着核心作用。最近，我们实验室 产生的UVRAG(紫外线耐辐射相关基因)突变小鼠表现出正常的基础水平 自噬，但在刺激诱导的自噬方面存在缺陷。通过这个小鼠模型，我们演示了 自噬失调可能会加剧炎症，促进自发性癌症。然而，梅杰 我们对自噬、炎症和癌症之间错综复杂的关系的理解仍然存在差距， 包括1)不充分的自噬维持炎症小体反应的机制是什么？ 并导致炎症相关的病理改变？2)基础自噬抑制如何影响组织 动态平衡和促进癌症易感性？该项目将通过专注于两个具体的项目来填补这些空白 目的：1)研究自噬功能障碍在炎症信号转导中的分子机制； 炎症相关病理；2)确定Wnt/b自噬抑制的分子机制。 连环蛋白信号激活与自发性肿瘤发生。这些目标将通过以下方式实现 多学科的创新方法，将最先进的遗传学、生物化学、单细胞分析、 以及在细胞、3D器官培养和小鼠中进行的生理测试，这些细胞和小鼠的基因与 UVRAG功能和自噬解除调控。总之，我们预计这些研究将阐明 自噬失衡、炎症失控和 自发的肿瘤发生，从而提供了重要的新的洞察力，以功能谱系 自噬和促进制定亟需的治疗炎症的新战略 病理学和癌症，尤其是与自噬缺陷相关的那些。

Project Summary Mounting evidence from our laboratory and others suggests that a lysosomal degradation pathway, called autophagy, plays a central role in orchestrating inflammation and cancer biology. Recently, our laboratory generated UVRAG (UV irradiation resistance associated gene) mutant mice that show normal levels of basal autophagy but are deficient in stimulus-induced autophagy. With this mouse model, we demonstrate that autophagy dysregulation could exacerbate inflammation and promote spontaneous cancers. However, major gaps still exist in our understanding of intricate relationship between autophagy, inflammation and cancer, including 1) what are the mechanisms by which inadequate autophagy perpetuates inflammasome response and drives inflammation-associated pathologies? and 2) how does basal autophagy suppression affect tissue homeostasis and promote cancer susceptibility? This project will fill these gaps by focusing on two Specific Aims, including 1) investigating molecular mechanism of autophagy dysfunction on inflammatory signaling and inflammation-associated pathologies; and 2) identifying molecular mechanism of autophagy inhibition in Wnt/b- catenin signaling activation and spontaneous tumorigenesis. These aims will be addressed using multidisciplinary innovative approaches that integrate state-of-the-art genetic, biochemistry, single cell analysis, and physiological assays in cells, 3D organoid culture, and mice with targeted mutations in genes related to UVRAG function and autophagy deregulation. Together, we anticipate that these studies will elucidate the mechanisms underlying the intricate dialog between imbalance of autophagy, uncontrolled inflammation, and spontaneous tumorigenesis, thereby providing important new insights into the functional repertoire of autophagy and facilitating the development of much-needed new strategies for the treatment of inflammatory pathologies and cancer, particularly those associated with autophagy defects.