Role of SCGN in Intestinal Immune Homeostasis

项目总结 我是西雅图大学儿科消化、肝病和营养科的助理教授。 德克萨斯大学西南医学中心。我的长期职业目标是成为一名独立的 研究炎症性肠病基因驱动因素的研究人员。炎症性肠病(IBD) 被认为是由遗传易感个体暴露在关键环境中造成的。然而，大部分 遗传易感性仍未得到解释。在这方面，对已定义的遗传变异的机械论研究 与IBD相关的药物可以帮助我们填补这些关键空白，并可能提供新的治疗靶点。 我之前曾报告过SCGN基因突变导致早发性溃疡性结肠炎。 SCGN编码分泌素，这是一种钙感受器，仅在神经内分泌谱系中表达，包括 肠内分泌细胞和肠道神经元，并参与圈套介导的分泌。经鉴定，该突变 在人类中导致SCGN-SNAP-25膜定位异常，导致激素分泌受损， 模仿完全丧失SCGN。SCGN缺乏可导致DSS结肠炎易感性增加。我们的数据 提示肠道神经系统可能是所观察到的结肠炎表型的原因。后续 初步数据表明，在小鼠中，Scgn的丢失导致肠上皮I型干扰素的过度激活 回应。 这一建议的中心假设是SCGN缺乏导致的神经内分泌功能障碍 通过干扰天然免疫反应，特别是I型干扰素在IBD发病机制中的作用 上皮细胞的激活。该项目的总体目标是研究SCGN在肠道炎症中的作用 通过以下具体目标： 目的1-确定SCGN依赖性肠炎的神经内分泌细胞系。 目的2-确定I型干扰素信号在SCGN相关性结肠炎易感性中的作用。 目的3-确定SCGN依赖的免疫调节因子 为了执行这个指导性职业发展奖中提出的工作，我发展了一个职业 利用UTSW的科学环境的发展计划，具体侧重于 肠道炎症活体模型和下一代测序数据相关技术的发展 分析。我召集了一个导师/咨询委员会，由经验丰富的临床和基础 专注于人类遗传学、肠道炎症和IBD的科学研究人员。我的主要导师，以斯拉博士 伯斯坦领导着这支队伍。总而言之，从这里提出的研究中获得的信息将有助于 免疫调节作用的一组细胞通常不被认为是关键的炎症介质，在 肠道，最终承诺推动我走向独立。

PROJECT SUMMARY I am an Assistant Professor in the Division of Pediatric Gastroenterology, Hepatology and Nutrition at The University of Texas Southwestern Medical Center. My long-term career goal is to become an independent researcher investigating genetic drivers of inflammatory bowel disease. Inflammatory bowel disease (IBD) is thought to result from critical environmental exposures in genetically susceptible individuals. However, much of the genetic susceptibility remains unaccounted for. In this regard, mechanistic studies of defined genetic variants associated with IBD can help us fill these critical gaps and may provide novel therapeutic targets. I have previously reported the identification of a mutation in the SCGN gene causing early-onset ulcerative colitis. SCGN encodes secretagogin, a calcium sensor exclusively expressed in neuroendocrine lineages, including enteroendocrine cells and gut neurons and participates in SNARE mediated secretion. The mutation identified in humans leads to abnormal SCGN-SNAP-25 membranous localization resulting in impaired hormone secretion, mimicking complete SCGN loss. Scgn deficiency in mice results in enhanced DSS colitis susceptibility. Our data suggests that the enteric nervous system might be responsible for the observed colitic phenotype. Subsequent preliminary data indicates that Scgn loss in mice results in hyperactivation of intestinal epithelial type I interferon response. The central hypothesis of this proposal is that neuroendocrine dysfunction resulting from SCGN deficiency plays a role in IBD pathogenesis through disruption of innate immune responses, specifically Type I interferon activation in the epithelium. The project’s overall goal is to study the role of SCGN in intestinal inflammation through the following specific aims: Aim 1 – To define the neuroendocrine lineage cells responsible for SCGN-dependent intestinal inflammation. Aim 2 – Determine the contribution of type I interferon signaling in SCGN-associated colitis susceptibility. Aim 3 – To identify SCGN-dependent immunoregulatory factors To carry out the work proposed in this mentored Career Development Award, I have developed a career development plan that takes advantage of the scientific environment at UTSW, with a specific focus on development of skills related to in-vivo models of intestinal inflammation and next-generation sequencing data analysis. I have brought together a mentorship/advisory committee composed of experienced clinical and basic science researchers with a focus on human genetics, intestinal inflammation and IBD. My main mentor, Dr. Ezra Burstein, leads this team. In summary, the information gained from the studies proposed here will shed light on the immune-regulatory role a group of cells not commonly thought to be key mediators of inflammation, have in the intestine, with the ultimate promise of propelling me towards independence.