Interaction of Retinoid X Receptors and NOD-Like Receptors in Colon Inflammation

描述(申请人提供)：慢性炎症性综合征的产生是遗传多态与环境、病原体和饮食相结合的结果。结肠炎是一种以结肠溃疡为特征的炎症性肠病(IBD)。IBD通常与炎性细胞因子的过度产生有关，炎性细胞因子受多种细胞信号通路和核因子-kB转录因子家族的激活调节。由于NOD2与Crohns病的遗传相关性，NLR(核苷酸结合域和富含亮氨酸重复或Nod样受体)家族蛋白在IBD研究中受到了极大的关注。我们发现，NLRP12是一个新的NLR家族成员，它通过多种机制抑制NF-kB的激活，包括诱导蛋白酶体介导的NIK(NF-kB诱导激酶)的降解，从而发挥炎症的负性调节作用。除了天然免疫的负性调节外，研究表明核受体(NRs)可以抑制炎症、肿瘤形成和诱导细胞凋亡。更深入地了解NLRP12如何与NRS相互作用，对于理解在维持肠道内稳态和减少健康肠道炎症中至关重要的过程是重要的。我们利用蛋白质互作组学分析发现，NLRP12可以与NRs相互作用。此外，我们还在NLRP12启动子中定位了几个潜在的NR调控元件。这项建议的目的是确定NRS和NLRP12在调节结肠中的NF-kB激活方面的交集。

DESCRIPTION (provided by applicant): Chronic inflammatory syndromes arise as a consequence of genetic polymorphism in combination with environment, pathogens and diet. Colitis is a form of inflammatory bowel diseases (IBD) that is characterized by ulcers in the colon. IBD are commonly associated with the exaggerated production of inflammatory cytokines, which are regulated by the activation of various cell signaling pathways and the NF-kB family of transcription factors. The NLR (nucleotide binding domain and leucine-rich-repeat-containing or NOD-like receptor) family of proteins has received much attention in IBD research due to the genetic association of NOD2 with Crohns' disease. We found that NLRP12, a new NLR family member acts as a negative regulator of inflammation by suppressing NF-kB activation via multiple mechanisms, including the induction of proteasome mediated degradation of NIK (NF-kB inducing kinase). In addition to negative regulators of innate immunity, studies have shown that nuclear receptors (NRs) can suppress inflammation, tumor formation, and induce cell apoptosis. A greater understanding of how NLRP12 can interact with NRs is important in understanding the processes that are crucial in the maintenance of homeostasis and the reduction of inflammation in a healthy gut. We employed an in silico protein interactome analysis and found that NLRP12 can interact with NRs. In addition, we localized several potential NR regulatory elements in the promoter of NLRP12. The goal of this proposal is to determine the intersection of NRs with NLRP12 in regulating NF-kB activation in colon.