NLRP12 Regulation of COX-2 in Colitis and Colon Cancer Development

描述（由申请人提供）：结直肠癌（CC）是美国癌症相关死亡的主要原因，是炎症性肠病（IBD）（如溃疡性结肠炎（UC））的主要并发症。IBD通常与炎性细胞因子的过度产生有关，其通过各种细胞信号传导途径和转录因子的NF-β B家族的活化来调节。NLR（nucleotide binding domain and leucine-rich-repeat-containing or NOD-like receptor）蛋白家族由于NOD 2与克罗恩病的遗传关联而在IBD研究中受到了广泛关注。我们发现NLRP 12是一个新的NLR家族成员，在单核细胞、粒细胞和树突状细胞中表达，并通过多种机制抑制NF-（B）活化，包括诱导蛋白酶体介导的NIK（NF-（B诱导激酶）降解，作为炎症的负调节因子。此外，NLRP 12的缺失导致NIK升高，导致考克斯-2的组成型表达，COX-2是负责前列腺素（PG）合成的限速酶的可诱导形式。考克斯-2的表达和PGE 2的产生在IBD和CC中升高，但它们在这些疾病发展中的确切作用有些争议。考克斯-2的缺失导致UC小鼠模型中结肠炎的易感性增加。然而，考克斯-2衍生的PGE 2促进结直肠癌的生长和侵袭，并且已经显示几种考克斯-2抑制剂抑制结直肠肿瘤的发展。来自我们实验室的初步数据表明，缺乏NLRP 12的小鼠比野生型小鼠更容易患结肠炎，并显示出更大的结肠肿瘤发生。尚不清楚这是否是由于升高的考克斯-2衍生的PG水平、增强的炎性细胞因子产生（例如IL-1（和IL-6）或这两种元素的组合。本研究的目的是探讨NLRP 12负调控的考克斯-2代谢产物和其他炎症因子在UC和CC发展中的作用，并确定NLRP 12调控NIK的机制。 目的1将检查NLRP 12是否调节UC和CC模型中的考克斯-2代谢物。目的2将检查NLRP 12对NIK和/或IRAK的调节是否在UC和/或CC的发展中起作用。目的3探讨NLRP 12对NIK通路的调控机制。

DESCRIPTION (provided by applicant): Colorectal cancer (CC) is a leading contributor to cancer-related deaths in the United States and is a major complication of inflammatory bowel diseases (IBD), such as ulcerative colitis (UC). 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-(B 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, is expressed in monocytes, granulocytes, and dendritic cells and acts as a negative regulator of inflammation by suppressing NF-(B activation via multiple mechanisms, including the induction of proteasome mediated degradation of NIK (NF-(B inducing kinase). Moreover, the loss of NLRP12 results in elevated NIK, leading to the constitutive expression of COX-2 which is the inducible form of the rate-limiting enzyme responsible for prostaglandin (PG) synthesis. COX-2 expression and PGE2 production are elevated in IBD and CC, yet their precise role in the development of these diseases is somewhat controversial. The absence of COX-2 leads to increased susceptibility of colitis in murine models of UC. However, COX-2-derived PGE2 promotes growth and invasion of colorectal carcinoma and several COX-2 inhibitors have been shown to suppress the development of colorectal tumors. Preliminary data from our lab indicates that mice lacking NLRP12 are significantly more susceptible to the development of colitis and display greater colon tumorigenesis than their wildtype counterparts. It is unclear if this is due to elevated COX-2-derived PG levels, enhanced inflammatory cytokine production (e.g. IL-1( and IL-6), or a combination of these two elements. The goal of this proposal is to explore the contribution of COX-2 metabolites and other inflammatory factors negatively regulated by NLRP12 in the development of UC and CC and to identify the mechanism behind NLRP12 regulation of NIK. Aim 1 will examine if NLRP12 regulates COX-2 metabolites in UC and CC models. Aim 2 will examine if the regulation of NIK and/or IRAK by NLRP12 plays a role in the development of UC and/or CC. Aim 3 will explore the mechanism by which NLRP12 regulates the NIK pathway.