GATA4 as a window into the link between metabolism and immunity

GATA4 作为代谢与免疫之间联系的窗口

• 批准号: 8715690
• 负责人: BANA JABRI
• 金额: $ 23.8万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-06 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8715690
• 关键词: Antigen-Antibody Complex; Area; Atherosclerosis; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Bacteria; Biological Models; Cell Line; Cells; Child; Clinical; Clinical Research; Clinical Trials; Complex; Data; Defect; Disease; Down-Regulation; Early Diagnosis; Early Intervention; Epithelial Cells; Epithelium; Equilibrium; Event; GATA4 transcription factor; Gene Expression; Gene Expression Profile; Genes; Germ-Free; Goals; Homeostasis; Human; Hypertension; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunology; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Insulin-Dependent Diabetes Mellitus; Intestines; Killer Cells; Lead; Link; Lipids; Mediating; Metabolic; Metabolism; Methods; Microbe; Mitochondria; Molecular Profiling; Mouse Cell Line; Mus; Organism; Pathogenesis; Pathway interactions; Play; Population; Process; Proteins; Regulation; Role; Sterility; System; Systems Biology; Techniques; Testing; Tissues; Translating; Up-Regulation; Wild Type Mouse; base; diabetes risk; intestinal epithelium; lipid metabolism; microbiome; pathogen; programs; public health relevance; response; small hairpin RNA; transcription factor

DESCRIPTION (provided by applicant): The events that initiate complex inflammatory and autoimmune disorders are largely unknown. In this proposal, we will test a new hypothesis that links metabolic disturbance and the intestinal microbiota with the initiation and/or dysregulation of intestinal immunity. Both the microbiota and metabolic defects have been implicated in immune disorders. The intestinal microbiota, for example, have been implicated in the pathogenesis of inflammatory bowel disease and autoimmune disorders such as type-1 diabetes, and recent clinical trials have suggested that early metabolic defects can be seen children at risk of Diabetes before any clinical signs of disease. Until recently it has been unclear how metabolic disturbances might underlie inflammatory/autoimmune disorders, but a recent discovery in mice suggests that there may be a direct link. Here we propose to characterize this link, and to assess what role the microbiota may play in translating a metabolic defect into an immune response. Mice whose intestinal epithelium is deficient for the transcription factor, GATA4, are defective in certain aspects of intestinal lipid metabolism and have been found to also have dysregulated intestinal immunity. The central hypothesis of this proposal, therefore, is that perturbations in metabolic processes lead to upregulation/dysregulation of immunity through two non-mutually exclusive pathways: 1) a change in the microbiota, caused by the metabolic perturbation, that disrupts the normal intestinal immune balance 2) a direct linkage between metabolic and immune gene networks. In specific aim 1 we will define the full range of gene expression differences between GATA4 deficient and sufficient mice, and then determine whether and how the microbiota may influence these differences. In specific aim 2 we will dissect, in a reductionist model system in vitro, the genes critical for cell intrinsic (microbe-independent) connections between the metabolic and immune networks. This project brings together two internationally recognized PIs, and two rising young systems biologist and microbiologist with unique and complementary expertise in fundamental immunology, intestinal immunity, the microbiome, and autoimmunity. The program described in this application will dissect a hitherto unknown pathway of immune initiation, and dysregulation that may underlie a number of autoimmune and inflammatory disorders.

描述（由申请人提供）：引发复杂炎症和自身免疫性疾病的事件在很大程度上未知。在此提案中，我们将检验一个新的假设，该假设将代谢障碍和肠道菌群与肠道免疫的起始和/或失调联系起来。 微生物群和代谢缺陷都与免疫疾病有关。例如，肠道菌群与炎症性肠病和自身免疫性疾病（如1型糖尿病）的发病机理有关，最近的临床试验表明，早期的代谢缺陷可以在任何临床疾病症状前都出现糖尿病的风险。直到最近，还尚不清楚代谢障碍如何构成炎症/自身免疫性疾病的基础，但是最近在小鼠中发现的发现可能存在直接联系。在这里，我们建议表征此链接，并评估微生物群在将代谢缺陷转化为免疫反应中可能起什么作用。 肠上皮缺乏转录因子GATA4的小鼠在肠道脂质代谢的某些方面有缺陷，并且也发现肠道免疫失调。因此，该提议的核心假设是，代谢过程中的扰动导致免疫的上调/失调通过两种非多余的排斥途径：1）由代谢扰动引起的微生物群的变化，这会破坏正常的无肠免疫平衡2）直接链接2）一种直接链接的基因和免疫网络和免疫网络之间的直接连锁。在特定目标1中，我们将定义GATA4缺乏和足够小鼠之间的全基因表达差异，然后确定微生物群是否以及如何影响这些差异。在特定目标2中，我们将在体外还原主义模型系统中剖析代谢网络和免疫网络之间对细胞内在（微生物独立）连接至关重要的基因。 该项目汇集了两个国际认可的PI，以及两名新兴的年轻系统生物学家和微生物学家，在基本免疫学，肠道免疫，微生物组和自身免疫方面具有独特和互补的专业知识。本应用程序中描述的程序将剖析迄今未知的免疫起始途径，并且可能是许多自身免疫性和炎症性疾病的失调。