Forward Genetic Analysis of Intestinal Homeostasis

肠道稳态的正向遗传学分析

基本信息

批准号：
9179527
负责人：
Emre Erol Turer
金额：
$ 14.4万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-04 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9179527
关键词：
AKT1 gene Affect Apoptosis Autophagocytosis Candidate Disease Gene Cell Death Cells Cellular Metabolic Process Ceramides Chronic Colitis Colon Crohn&apos s disease Defect Development Emergency Situation Environmental Risk Factor Enzymes Epithelial Epithelial Cells Equilibrium Etiology Exhibits Genes Genetic Genetic Screening Goals Growth Health Healthcare Hemorrhage Hospitalization Human Human Genetics Immune Immune response Immune system Infection Infiltration Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Integration Host Factors Intestinal Diseases Intestines Lead Lipids MAPK8 gene Maintenance Maps Metabolic Metabolism Mitochondria Molecular Mouse Strains Mus Mutagenesis Mutate Names Nature Operative Surgical Procedures Organism Pain Pathology Pathway interactions Permeability Phenotype Play Predisposition Production Regulation Relapse Reporting Research Resistance Role Signal Transduction Small Intestines Sodium Dextran Sulfate Sphingolipids System Testing Ulcerative Colitis United States Variant abstracting conditioning cytokine desaturase enzyme biosynthesis exome sequencing gene synthesis genetic analysis genetic approach immune activation in vivo insight intestinal homeostasis large bowel Crohn&apos s disease lipid mediator microbial mitochondrial metabolism mortality mouse model mutant novel novel therapeutic intervention paracrine pathogen pleiotropism whole genome

项目摘要

Abstract Inflammatory bowel disease is a debilitating chronic condition, which can affect any part of the intestine, often having by a relapsing and remitting course. In the United States, there are approximately 1.4 million people are affected by ulcerative colitis or Crohn's disease. The resulting inflammation in the colon and small intestine can lead to pain, infections and bleeding, which ultimately leads to a healthcare burden of increased hospitalizations, emergency surgeries and most importantly increased mortality. Although a hyper- inflammatory response to the intestinal micro flora certainly plays a role in the etiology of IBD, the exact etiology of inflammatory bowel disease, however, is not well understood and is most certainly multifactorial in nature. The maintenance of the mucosal immune system has many levels as has been seen in human genetics and experimental mouse models. These systems include immune and growth factor as well as epithelial proliferation, apoptosis, autophagy and cellular metabolism. Perturbation of any of these systems results in a defect of intestinal homeostasis and ultimately resulting in pathology. My recent studies have looked at the genetic factors necessary for maintaining intestinal homeostasis. Using a screen of randomly mutagenized mice, I have identified and mapped candidate genes for over 30 novel mouse strains that show either susceptibility or resistance to mouse experimental colitis. One such unexpected pathway involves the de novo synthesis of ceramide and phytoceramide. I plan to use genetically modified mice in which a key ceramide metabolic gene (Degs2) is deleted or mutated to elucidate a mechanistic understanding of these pathways and their regulation. The ultimate goal of my research is to determine new pathways, which can be targeted to better treat intestinal diseases, such as Crohn's and ulcerative colitis.

抽象的炎症性肠病是一种使人衰弱的慢性疾病，可影响肠道的任何部位。肠道，通常有复发和缓解过程。在美国，大约有 1.4 数百万人患有溃疡性结肠炎或克罗恩病。由此产生的结肠炎症小肠会导致疼痛、感染和出血，最终导致医疗负担住院治疗、紧急手术的增加，最重要的是死亡率的增加。虽然是超对肠道微生物菌群的炎症反应肯定在 IBD 的病因学中发挥着一定作用，确切的说然而，炎症性肠病的病因尚不清楚，并且肯定是多因素影响的自然。正如在人类中所见，粘膜免疫系统的维持有多个层面遗传学和实验小鼠模型。这些系统包括免疫和生长因子以及上皮增殖、凋亡、自噬和细胞代谢。对任何这些系统的扰动导致肠道稳态缺陷并最终导致病理。我最近的研究着眼于维持肠道稳态所需的遗传因素。通过随机诱变小鼠的筛选，我已经识别并绘制了 30 多个候选基因对小鼠实验性结肠炎表现出易感性或抗性的新型小鼠品系。这样的一位意想不到的途径涉及神经酰胺和植物神经酰胺的从头合成。我打算用基因修饰小鼠，其中关键的神经酰胺代谢基因（Degs2）被删除或突变，以阐明其机制了解这些途径及其调节。我研究的最终目标是确定新的途径，可以更好地治疗肠道疾病，如克罗恩病和溃疡性结肠炎。