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

项目摘要/摘要 应激后胃肠道的平衡并恢复到平衡状态(传染性， 化学或其他方面)是调节许多人类肠道疾病的关键决定因素，包括那些 自身免疫性和感染性来源。也许研究得最好的遗传性肠病是炎症性肠病 疾病(IBD)，然而，IBD的确切病因还不完全清楚。为了更好地了解肠道 免疫动态平衡，我们进行了一项正向基因筛查，以无偏见地识别这些必要的基因 非冗余功能。到目前为止，我们已经使用这种方法检查了49,690只小鼠，它们是一个储存库 在19368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 从一些广泛的功能类别的基因突变，包括经典的免疫基因，生长 因子和细胞外基质蛋白，以及预期功能较差的基因突变，如 作为囊泡运输和新陈代谢。我们选择检测基因的一个子集(Smcr8和Wdr41) 引起显著的表型，并与C9orf72一起存在于与泡囊相连的同一大分子复合体中 运输。Smcr8-Wdr41-C9orf72(SWC)复合体是一种三方鸟嘌呤核苷酸交换因子，它 站在多条人类疾病途径、炎症信号、自噬和 溶酶体运输。在这个提案中，我们将研究调节细胞和分子的成分 SWC复合体缺乏症的功能障碍及其导致的三个特殊目的的病理：(1)检查 需要SWC复合体来调节肠道和外周炎症的细胞成分。(2)至 了解内体TLR的分子机制、信号通路和体内后果 SWC缺乏症的调节失调。(3)研究深港西部通道综合设施的调节机制 吞噬小体成熟。这项提案的目的将有助于阐明 溶酶体成熟到炎症信号之间的串扰，从而扩大了我们对 IBD等胃肠疾病的发病机制。

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.