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

Smcr8-Wdr41-C9orf72 (SWC) 复合物在维持肠道稳态中的作用

基本信息

批准号：
10569106
负责人：
Emre Erol Turer
金额：
$ 43.37万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569106
关键词：
Affect Alleles Animals Autoimmune Autophagocytosis Bacteria Biological Biological Models Bone Marrow C9ORF72 Categories Cell physiology Cells Chemicals Chronic Code Colitis Complex Dendritic Cells Development Disease Pathway Disparate Endosomes Equilibrium Essential Genes Ethylnitrosourea Etiology Exhibits Extracellular Matrix Proteins FRAP1 gene Functional disorder Gastrointestinal Diseases Gastrointestinal tract structure Genes Genetic Screening Genetic study Goals Growth Factor Guanine Nucleotide Exchange Factors Health Care Costs Homeostasis Human Immune Immune signaling Immune system Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Innate Immune System Intestinal Diseases Intestines Knowledge Link Lysosomes MAP Kinase Gene Macromolecular Complexes Macrophage Maintenance Maps Mediating Metabolism Methods Microbe Molecular Mus Mutagens Mutation Pathology Pathway interactions Peripheral Persons Phagocytosis Phagolysosome Phenotype Play Predisposition Production Proto-Oncogene Proteins c-akt RNA Splicing Receptor Signaling Role Signal Pathway Signal Transduction Stimulus Stress T-Lymphocyte TLR3 gene Tissues Toll-like receptors United States Vesicle Visualization Work cell type cytokine dextran sulfate sodium induced colitis gut inflammation human disease in vivo insight intestinal epithelium intestinal homeostasis microbial mouse model mutant pathogen pathogenic bacteria prevent response trafficking vesicle transport

项目摘要

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.

项目概要/摘要胃肠道的平衡，并在压力（传染性、化学或其他）是调节许多人类肠道疾病的关键决定因素，包括那些自身免疫和感染起源。也许研究得最好的遗传性肠道疾病是炎症性肠病然而，IBD 的确切病因尚不完全清楚。为了更好的了解肠道为了免疫稳态，我们进行了正向遗传筛选，以公正地识别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 只作为储存库的小鼠 19,368 个基因的编码或剪接中的 104,845 个突变等位基因。对实验性结肠炎结果的易感性来自许多广泛功能类别的基因突变，包括经典免疫基因、生长因子和细胞外基质蛋白以及具有不太预期功能的基因突变，例如如囊泡运输和新陈代谢。我们选择检查基因的子集（Smcr8 和 Wdr41）引起显着的表型，并与 C9orf72 一起存在于与囊泡相连的同一大分子复合物中运输。 Smcr8-Wdr41-C9orf72 (SWC) 复合物是一种三联鸟嘌呤核苷酸交换因子，处于多种人类疾病途径、炎症信号、自噬和溶酶体运输。在本提案中，我们将检查介导细胞和分子的成分 SWC 复合体缺乏症的功能障碍以及由此产生的三个具体目标的病理学：（1）检查细胞成分需要 SWC 复合物来调节肠道和外周炎症。 (2) 至了解内体 TLR 的分子机制、信号通路和体内后果 SWC 缺乏导致的失调。 (3) 考察SWC复合物的调节机制吞噬溶酶体成熟。该提案的目标将有助于阐明潜在的机制溶酶体成熟与炎症信号传导之间的串扰，从而扩展了我们对溶酶体成熟与炎症信号传导之间的串扰 IBD 等胃肠道疾病的潜在机制。