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

描述(申请人提供)：结直肠癌(CC)是美国癌症相关死亡的主要原因，也是炎症性肠道疾病(IBD)的主要并发症，如溃疡性结肠炎(UC)。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-B家族转录因子的激活调节。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，表达于单核细胞、粒细胞和树突状细胞，通过多种机制抑制NF-B的激活，包括诱导蛋白酶体介导的NIK(NF-B诱导激酶)的降解，作为炎症的负性调节因子。此外，NLRP12的缺失导致NIK升高，导致COX-2的结构性表达，COX-2是负责合成前列腺素(PG)的限速酶的诱导形式。COX-2表达和PGE2产物在IBD和CC中升高，但它们在这些疾病发生发展中的确切作用尚有争议。在UC的小鼠模型中，COX-2的缺失导致结肠炎易感性增加。然而，COX-2衍生的PGE2促进结直肠癌的生长和侵袭，几种COX-2抑制剂已被证明抑制结直肠癌的发展。我们实验室的初步数据表明，缺乏NLRP12的小鼠比野生型小鼠更容易患结肠炎，并表现出更大的结肠肿瘤发生。目前尚不清楚这是由于COX-2衍生的PG水平升高、炎性细胞因子(例如IL-1(和IL-6))的产生增加，还是这两种因素的组合。本研究的目的是探讨NLRP12负性调控的COX-2代谢产物和其他炎症因子在UC和CC发生发展中的作用，以及NLRP12调控NIK的机制。 目的1研究NLRP12在UC和CC模型中是否调节COX-2代谢产物。目标2将研究NLRP12对NIK和/或IRAK的调节是否在UC和/或CC的发展中发挥作用。目的3探讨NLRP12调控NIK通路的机制。 公共卫生相关性：更好地了解NLRP12调节NIK的机制，以及NIK诱导的COX-2如何促进结肠炎和结肠癌的易感性和发展，将为预防和/或治疗这些疾病提供更好的见解。这些目标的成功完成可能会支持将NLRP12添加到目前多家制药公司靶向的NLR基因名单中。

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. PUBLIC HEALTH RELEVANCE: A better understanding of the mechanisms by which NLRP12 regulates NIK and how NIK-induced COX-2 contributes to the susceptibility and development of colitis and colon cancer will provide better insights for the prevention and/or treatment of these diseases. Successful completion of these goals may support the addition of NLRP12 to the list of NLR genes currently being targeted by multiple pharmaceutical companies.