A20 (TNFAIP3) Regulation of Intestinal Immune Homeostasis

描述（由申请人提供）：核因子(NF)-kB信号对于维持肠道免疫稳态很重要。不适当的NF-kB活性导致炎症性肠病（IBD），因此必须严格调节。泛素修饰蛋白A20（也称为TNFa诱导蛋白3，TNFAIP3）是NF-kB信号传导的关键调节因子，A20缺陷小鼠因自发性全身炎症和恶病质而发生自发性肠道炎症和围产期死亡。最近的遗传学研究已经确定TNFAIP3是与炎症性肠病相关的候选基因。因此，了解A20如何调节肠道免疫稳态对于理解IBD的发病机制和开发IBD患者的新疗法至关重要。A20是一种独特的泛素修饰酶，具有去泛素化和泛素连接酶活性。初步数据表明，A20在限制TNF、TLR和NOD信号传导，预防自发性肠道炎症和IBD中起关键作用。本研究有三个具体目的：1)表征和定义A20泛素修饰域如何限制肿瘤坏死因子（TNF）信号传导；2)表征和定义A20泛素修饰域如何限制toll样受体（TLR）信号传导；3)确定A20泛素修饰域如何参与限制小鼠模型中炎症性肠病的发展。这些研究将为A20如何限制炎症信号级联反应和调节肠道免疫稳态提供机制见解。这些研究将为开发IBD的新疗法提供潜在的新线索。拟议的研究将在马亚伟博士的指导下进行。职业发展计划包括教学课程、研究研讨会和演讲、期刊俱乐部，以及拟议的研究出版物和职业时间表。由国际公认的IBD、免疫学、人类遗传学和细胞凋亡生物学领域的导师、合作者和顾问组成的职业发展委员会将有助于确保卢博士达到所提出的里程碑。拟议的研究将为R01拨款奠定坚实的基础，并使陆博士成为粘膜免疫学和IBD的独立研究者。

DESCRIPTION (provided by applicant): Nuclear Factor (NF)-kB signaling is important for the maintenance of intestinal immune homeostasis. Inappropriate NF-kB activity results in inflammatory bowel disease (IBD) and thus must be tightly regulated. The ubiquitin-modifying protein A20 (also known as TNFa induced protein 3, TNFAIP3) is a critical regulator of NF-kB signaling as demonstrated by A20-deficient mice which develop spontaneous intestinal inflammation and die perinatally due to spontaneous systemic inflammation and cachexia. Recent genetic studies have identified TNFAIP3 as a candidate gene associated with inflammatory bowel disease. Therefore, an understanding of how A20 regulates intestinal immune homeostasis will be critical in understanding the pathogenesis of IBD and the development of novel therapeutics for patients with IBD. A20 is a unique ubiquitin-modifying enzyme with both deubiquitinating and ubiquitin ligase activity. Preliminary data suggests that A20 is critical in restricting TNF, TLR and NOD signaling and preventing in spontaneous intestinal inflammation and IBD. The proposed research has three specific aims: 1) characterize and define how the A20 ubiquitin modifying domains restrict tumor necrosis factor (TNF) signaling, 2) characterize and define how the A20 ubiquitin modifying domains restrict toll-like receptor (TLR) signaling, and 3) determine how the A20 ubiquitin modifying domains are involved in restricting the development of inflammatory bowel disease in mouse models. These studies will provide mechanistic insight into how A20 restricts inflammatory signaling cascades and regulates intestinal immune homeostasis. These studies will provide potential new leads for the development of novel therapeutics for IBD. The proposed studies will be undertaken with the mentorship of Dr. Averil Ma. A Career Development Plan including didactic courses, research seminars and presentations, and journal clubs has been developed along with a proposed research publication and career timeline. A career development committee of internationally recognized mentors, collaborators, and advisors with expertise in the fields of IBD, immunology, human genetics and apoptosis biology will help ensure that Dr. Lu meets the proposed milestones. The proposed studies will establish a firm foundation for an R01 grant and allow Dr. Lu to become an independent investigator in mucosal immunology and IBD. PUBLIC HEALTH RELEVANCE: Human genetic studies have identified TNFAIP3, which encodes for the protein A20, as a gene associated with inflammatory bowel disease and other autoimmune diseases. In this research proposal, our goals are to understand how A20 regulates the immune system and susceptibility to inflammatory bowel disease and other autoimmune diseases. These studies will provide new insights into the development of targeted therapies for inflammatory bowel disease patients. )