SREBP-Mediated Regulation of Intestinal Epithelial Homeostasis

SREBP 介导的肠上皮稳态调节

基本信息

批准号：
9982905
负责人：
Luke James Engelking
金额：
$ 42.28万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982905
关键词：
Ablation Affect Anabolism Binding Proteins Biological Assay Cardiovascular system Cell Compartmentation Cell Death Cells Cholesterol Clinical Colorectal Cancer Cre-LoxP Development Diet Dietary Fats Differentiation and Growth Enzymes Epidemic Epithelial Epithelial Cells Epithelium Equilibrium Event Fatty Acid Desaturases Fatty Acids Fatty acid glycerol esters Gastrointestinal Diseases Gene Expression Genes Genetic Goals Growth Health High Fat Diet Homeostasis Hyperplasia Hypertriglyceridemia Hypertrophy In Vitro Injury Intestinal Cancer Intestinal Neoplasms Intestines Knock-out Lipids Malignant neoplasm of gastrointestinal tract Measurement Mediating Messenger RNA Metabolism Molecular Morbidity - disease rate Mus Obesity Organ Size Organoids Outcome Pathway interactions Pharmacology Public Health Regulation Regulatory Element Research Risk Factors Role SRE-1 binding protein SRE-2 binding protein Small Intestines Sterols Stimulus Testing Therapeutic Intervention Ursidae Family Work anti-cancer base cell type crypt cell experimental study falls gene product improved in vitro testing in vivo intestinal crypt intestinal epithelium intestinal homeostasis lipid biosynthesis lipid metabolism mouse model new therapeutic target non-alcoholic fatty liver disease novel overexpression progenitor proteostasis stem cells therapeutic development tool transcription factor transcriptome transcriptome sequencing transcriptomics translational impact uptake

项目摘要

Obesity is rapidly on the rise and is associated with dysregulated metabolism, cardiovascular morbidity and increased rates of gastrointestinal malignancies. Moreover, obesity is driven by high-fat, high-cholesterol diets that are themselves serious risk factors for gastrointestinal cancers. The most rapidly-dividing cells in the body reside in the intestinal epithelium, which relies on progenitor cells like intestinal stem cells (ISCs) to sustain it. While dietary lipids are known to regulate ISCs, the mechanisms by which lipids affect intestinal proliferation are not well understood. Lipid biosynthesis is regulated by sterol regulatory element-binding proteins (SREBPs). My recent studies have demonstrated that SREBPs also have a critical role in sustaining growth of the intestinal epithelia. I found, surprisingly, that a deficiency of SREBP-2, which blocks cholesterol synthesis, results in marked intestinal overgrowth and increased numbers of intestinal progenitor cells. I hypothesized that this increase in proliferatory capacity of the intestine was caused by a compensatory stimulation of SREBP-1 in the SREBP-2 knockouts. Next, I found that overexpression of SREBP-1 in intestine reproduced this intestinal overgrowth, confirming that SREBP-1, which controls fatty acid synthesis, is a key regulator of intestinal epithelial growth. The goal of this proposal is to determine the molecular mechanisms by which SREBPs controls intestinal epithelial proliferation. The central hypothesis is that SREBPs maintain homeostasis of intestinal epithelia by producing lipid metabolites that sustain proliferation of intestinal progenitors. Thus, the following specific aims will be pursued: (1) To determine how SREBP-1 drives the growth of intestinal epithelia. (2) To identify the cellular compartment(s) where SREBPs mediate their effects on intestinal growth. (3) Using unbiased transcriptome and lipidome profiling, to identify the lipid metabolites and their biosynthetic enzymes that underlie the effects of SREBPs on the epithelium. These aims will be achieved with novel mouse models using Cre-loxP tools to modulate gene and marker expression in intestine in vivo, RNA-seq and lipidomics measurements, and intestinal organoids for in vitro mechanistic experiments. The expected outcome of this proposal is the identification of mechanisms by which SREBPs regulates intestinal growth. This outcome will have positive translational impact because it is feasible that the newly-identified lipid regulators will represent novel therapeutic targets that could be manipulated pharmacologically. Growth stimuli could be inhibited in the setting of intestinal cancers for anti-cancer effect or stimulated in the setting of short bowel. Lastly, a better understanding of intestinal lipid metabolism in the intestine will facilitate the development of new treatments for complications of obesity like NAFLD, which is epidemic in the U.S.

肥胖率迅速上升，并与代谢失调、心血管发病率和胃肠道恶性肿瘤发病率增加有关。此外，肥胖是由高脂肪、高胆固醇饮食造成的，这些饮食本身就是胃肠道癌症的严重危险因素。体内分裂最快的细胞位于肠上皮细胞中，肠上皮细胞依靠肠干细胞 (ISC) 等祖细胞来维持。虽然已知膳食脂质可以调节 ISC，但脂质影响肠道增殖的机制尚不清楚。脂质生物合成由甾醇调节元件结合蛋白（SREBP）调节。我最近的研究表明，SREBP 在维持肠上皮细胞生长方面也发挥着关键作用。令人惊讶的是，我发现 SREBP-2 的缺乏会阻碍胆固醇的合成，导致肠道明显过度生长和肠道祖细胞数量增加。我推测肠道增殖能力的增加是由 SREBP-2 敲除中 SREBP-1 的代偿性刺激引起的。接下来，我发现肠道中 SREBP-1 的过度表达再现了这种肠道过度生长，证实了控制脂肪酸合成的 SREBP-1 是肠上皮生长的关键调节因子。该提案的目的是确定 SREBP 控制肠上皮增殖的分子机制。核心假设是，SREBP 通过产生维持肠道祖细胞增殖的脂质代谢物来维持肠上皮细胞的稳态。因此，将追求以下具体目标：（1）确定SREBP-1如何驱动肠上皮细胞的生长。 (2) 确定 SREBP 在其中介导其对肠道生长的影响的细胞区室。 (3) 使用无偏差的转录组和脂质组分析，鉴定构成 SREBP 对上皮细胞影响的脂质代谢物及其生物合成酶。这些目标将通过使用 Cre-loxP 工具调节体内肠道基因和标记物表达、RNA-seq 和脂质组学测量以及用于体外机械实验的肠道类器官的新型小鼠模型来实现。该提案的预期结果是确定 SREBP 调节肠道生长的机制。这一结果将产生积极的转化影响，因为新发现的脂质调节剂可能代表可以药理学操纵的新治疗靶点。在肠癌的情况下可以抑制生长刺激以达到抗癌作用，在短肠的情况下可以刺激生长刺激。最后，更好地了解肠道内的脂质代谢将有助于开发针对肥胖并发症的新疗法，例如在美国流行的 NAFLD。