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

描述（由申请人提供）：慢性炎症综合征是遗传多态性与环境，病原体和饮食结合的结果。结肠炎是一种炎症性肠病（IBD），其特征是结肠溃疡。IBD通常与炎症细胞因子的过度产生有关，炎症细胞因子受各种细胞信号通路和NF-kB转录因子家族的激活调节。由于NOD2与克罗恩病的遗传关联，NLR（核苷酸结合域和富含亮氨酸的重复序列或nod样受体）蛋白家族在IBD研究中受到了广泛关注。我们发现NLRP12，一个新的NLR家族成员，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，作为炎症的负调节因子。除了先天免疫的负调节因子外，研究表明核受体（NRs）还可以抑制炎症、肿瘤形成和诱导细胞凋亡。更好地了解NLRP12如何与NRs相互作用，对于理解维持健康肠道内平衡和减少炎症的关键过程至关重要。我们采用了硅蛋白相互作用组分析，发现NLRP12可以与rna相互作用。此外，我们在NLRP12的启动子中定位了几个潜在的NR调控元件。本提案的目的是确定NRs与NLRP12在调节结肠中NF-kB激活中的交集。

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.