GATA4 as a window into the link between metabolism and immunity

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是未知的。在这项提案中，我们将测试一个新的假设，该假设将代谢紊乱和肠道微生物群与肠道免疫的启动和/或失调联系起来。 微生物群和代谢缺陷都与免疫紊乱有关。例如，肠道微生物群与炎症性肠病和自身免疫性疾病（如1型糖尿病）的发病机制有关，最近的临床试验表明，在任何疾病的临床症状之前，早期代谢缺陷可以被视为糖尿病风险的儿童。直到最近，人们还不清楚代谢紊乱如何成为炎症/自身免疫性疾病的基础，但最近在小鼠身上的发现表明可能存在直接联系。在这里，我们建议描述这种联系，并评估微生物群在将代谢缺陷转化为免疫反应中可能发挥的作用。 肠上皮细胞缺乏转录因子GATA 4的小鼠在肠脂质代谢的某些方面有缺陷，并且已经发现还具有失调的肠免疫。因此，该提议的中心假设是代谢过程中的扰动通过两个非相互排斥的途径导致免疫的上调/失调：1）由代谢扰动引起的微生物群的变化，其破坏正常的肠道免疫平衡2）代谢和免疫基因网络之间的直接联系。在具体目标1中，我们将定义GATA 4缺陷和充足小鼠之间基因表达差异的全部范围，然后确定微生物群是否以及如何影响这些差异。在具体目标2中，我们将在体外简化模型系统中剖析代谢和免疫网络之间细胞内在（不依赖微生物）连接的关键基因。 该项目汇集了两名国际公认的PI，以及两名年轻的系统生物学家和微生物学家，他们在基础免疫学，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。本申请中描述的程序将剖析免疫启动的迄今未知途径，以及可能是许多自身免疫性和炎性疾病的基础的失调。

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.