Role of SCGN in Intestinal Immune Homeostasis

SCGN 在肠道免疫稳态中的作用

• 批准号: 10364664
• 负责人: Luis Sifuentes-Dominguez
• 金额: $ 16.74万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-10 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364664
• 关键词: ACTL6B gene; Advisory Committees; Affect; American; Anti-Inflammatory Agents; Attention; Basic Science; Biological Models; CDX2 gene; Calcium; Candidate Disease Gene; Cell Compartmentation; Cell Lineage; Cells; Childhood; Chronic; Clinical Sciences; Colitis; Complex; Data; Data Analyses; Development Plans; Disease; Endocrine; Enteral; Enteric Nervous System; Enteroendocrine Cell; Environment; Environmental Exposure; Epithelial; Foundations; Functional disorder; Gastroenterology; Gene Mutation; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic study; Goals; Hepatology; Homeostasis; Hormone secretion; Human; Human Genetics; Immune; Impairment; In Vitro; Individual; Inflammation Mediators; Inflammatory Bowel Diseases; Innate Immune Response; Interferon Activation; Interferon Type I; Interferons; Interleukin-10; Intestines; K-Series Research Career Programs; Light; LoxP-flanked allele; Mediating; Medical center; Mentors; Mentorship; Mind; Missense Mutation; Modeling; Mus; Mutation; Nervous system structure; Neuroendocrine Cell; Neurons; Neurosecretory Systems; Pathogenesis; Pathogenicity; Phenotype; Play; Population; Predisposition; Property; Proteins; Regulation; Reporting; Research; Research Personnel; Ribosomes; Risk Factors; Role; S-nitro-N-acetylpenicillamine; SNAP receptor; Secretory Vesicles; Signal Transduction; Syndrome; Technology; Texas; Tissues; Ulcerative Colitis; Universities; Work; career; career development; dextran sulfate sodium induced colitis; drug development; early onset; experience; experimental study; genetic variant; gut inflammation; immunoregulation; in vivo; in vivo Model; interest; intestinal epithelium; knockout animal; mouse model; new therapeutic target; next generation sequencing; novel therapeutic intervention; nutrition; professor; response; sensor; skill acquisition; transcriptome sequencing; type I interferon receptor; vesicular release; villin

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.

项目摘要 我是儿科胃肠病学，肝病学和营养学系的助理教授， 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 研究炎症性肠病的遗传驱动因素的研究人员。炎症性肠病（IBD）是 被认为是由遗传易感个体的关键环境暴露引起的。然而，许多 遗传易感性仍然不明。在这方面，确定的遗传变异的机制研究 与IBD相关的疾病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。 我以前曾报道过SCGN基因突变导致早发性溃疡性结肠炎的鉴定。 SCGN编码促分泌素，一种仅在神经内分泌谱系中表达的钙传感器，包括 肠内分泌细胞和肠道神经元并参与SNARE介导的分泌。发现的突变 导致异常的SCGN-SNAP-25膜定位，导致激素分泌受损， 模拟完全SCGN丧失。小鼠Scgn缺乏导致DSS结肠炎易感性增强。我们的数据 提示肠神经系统可能是观察到的结肠炎表型的原因。后续 初步数据表明，小鼠Scgn缺失导致肠上皮I型干扰素过度活化 反应 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发挥作用。 通过破坏先天免疫应答，特别是I型干扰素，在IBD发病机制中发挥作用 激活上皮细胞。该项目的总体目标是研究SCGN在肠道炎症中的作用 具体目标如下： 目的1 -确定负责SCGN依赖性肠道炎症的神经内分泌谱系细胞。 目的2 -确定I型干扰素信号在SCGN相关结肠炎易感性中的作用。 目的3 -鉴定SCGN依赖性免疫调节因子 为了开展这项指导性职业发展奖中提出的工作，我开发了一个职业生涯， 发展计划，利用UTSW的科学环境，特别注重 开发与肠道炎症体内模型和下一代测序数据相关的技能 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 科学研究人员专注于人类遗传学，肠道炎症和IBD。我的主要导师以斯拉博士 伯斯坦领导着这个团队。总之，从这里提出的研究中获得的信息将有助于阐明 一组通常不被认为是炎症关键介质的细胞在免疫调节中的作用， 肠子，最终承诺推动我走向独立。