The Role of the Smcr8-Wdr41-C9orf72 (SWC) Complex in the Maintenance of Intestinal Homeostasis

项目总结/摘要 胃肠道的平衡和恢复到平衡状态后的时间的压力（传染性， 化学的或其它的）是调节许多人类肠道疾病的关键决定因素， 自身免疫性和感染性起源。也许最好的研究遗传性肠道疾病是炎症性肠病 然而，IBD的确切病因学尚未完全了解。为了更好地了解肠道 免疫稳态，我们进行了正向遗传筛选，以无偏地鉴定这些必需基因， 非冗余功能。迄今为止，我们已经使用这种方法检查了49，690只小鼠，这些小鼠充当了宿主 在19，368个基因的编码或剪接中有104，845个突变等位基因。对实验性结肠炎结果的敏感性 从基因突变在一些广泛的功能类别，包括经典的免疫基因，生长 因子和细胞外基质蛋白以及来自具有较少预期功能的基因突变， as vesicular囊泡trafficking运输and metabolism代谢.我们选择检测一组基因（Smcr 8和Wdr 41）， 引起显著的表型，并与C9 orf 72沿着存在于与囊泡连接的相同大分子复合物中。 运输Smcr 8-Wdr 41-C9 orf 72（SWC）复合物是一种三方鸟嘌呤核苷酸交换因子， 站在多种人类疾病途径的交叉点，炎症信号，自噬， 溶酶体转运在这个建议中，我们将研究介导细胞和分子的组分， SWC复合体缺陷的功能障碍和由此产生的病理学有三个具体目的：（1）检查 需要SWC复合物来调节肠道和外周炎症的细胞组分。(2)到 了解内体TLR的分子机制，信号通路和体内后果 SWC缺陷的失调。(3)研究SWC复合物调节 吞噬溶酶体成熟本建议的目的将有助于阐明 溶酶体成熟与炎症信号传导之间的串扰，从而扩展了我们对 胃肠道疾病如IBD的潜在机制。

PROJECT SUMMARY/ABSTRACT The balance of the gastrointestinal tract and return to a state of equilibrium after times of stress (infectious, chemical or otherwise) is a critical determinant in regulating many human intestinal disorders including those of autoimmune and infectious origins. Perhaps the best studied genetic intestinal disorder is inflammatory bowel disease (IBD), however, the exact etiology of IBD is not fully understood. In order to better understand intestinal immune homeostasis, we carried out a forward genetic screen to unbiasedly identify these essential genes with non-redundant functions. To date, we have used this method to examine 49,690 mice, which serve as a reservoir for 104,845 mutant alleles in the coding or splicing of 19,368 genes. Susceptibility to experimental colitis results from mutations in genes in a number of broad functional categories, including classical immune genes, growth factors, and extracellular matrix proteins as well as from mutations in genes with less expected functions such as vesicular trafficking and metabolism. We have chosen to examine a subset of genes (Smcr8 and Wdr41) that cause a striking phenotype and exist along with C9orf72 in the same macromolecular complex linked to vesicular transport. The Smcr8-Wdr41-C9orf72 (SWC) complex is a tripartite guanine nucleotide exchange factor that stands at the intersection of multiple human disease pathways, inflammatory signaling, autophagy, and lysosomal transport. In this proposal, we will examine the components that mediate the cellular and molecular dysfunction in SWC complex deficiency and the resulting pathology in three Specific Aims: (1) To examine cellular components requiring the SWC complex for regulating intestinal and peripheral inflammation. (2) To understand the molecular mechanism, signaling pathways and in vivo consequences of endosomal TLR dysregulation in SWC deficiency. (3) To examine the mechanism by which the SWC complex regulates phagolysosomal maturation. The aims in this proposal will help elucidate the mechanisms underlying the crosstalk between lysosomal maturation to inflammatory signaling and thus expand our knowledge of the mechanisms underlying gastrointestinal disorders such as IBD.