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：
10623325
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/10623325
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 Cells Epithelium Equilibrium Event Fatty Acid Desaturases Fatty Acid-Binding Protein 1 Fatty Acids Fatty acid glycerol esters Gastrointestinal Diseases Gene Expression Genes Genetic Goals Growth Health High Fat Diet Homeostasis Human Hyperplasia Hypertriglyceridemia Hypertrophy In Vitro Injury Intestinal Cancer Intestines Knock-out Lipids Malignant neoplasm of gastrointestinal tract Measurement Mediating Messenger RNA Metabolism Molecular Morbidity - disease rate Mus Neoplasms Obesity Organ Size Organoids Outcome Pathway interactions Proliferating Public Health Regulation Regulatory Element Research Risk Factors Role SRE-1 binding protein SRE-2 binding protein Small Intestines Sterols Stimulus Testing Therapeutic Intervention Work anti-cancer 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 lipidome lipidomics mouse model new therapeutic target non-alcoholic fatty liver disease novel overexpression pharmacologic 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.

肥胖迅速上升，与代谢失调，心血管发病率和胃肠道恶性肿瘤发生率增加有关。此外，肥胖是由高脂，高胆固醇饮食驱动的，这些饮食本身就是胃肠道癌的严重危险因素。体内最快速分散的细胞居住在肠上皮中，该细胞依赖于肠道干细胞（ISC）等祖细胞来维持它。虽然已知饮食脂质可以调节ISC，但脂质影响肠道增殖的机制尚不清楚。脂质生物合成受固醇调节元素结合蛋白（SREBPS）调节。我最近的研究表明，SREBP在维持肠上皮的生长中也具有关键作用。我发现令人惊讶的是，阻断胆固醇合成的SREBP-2缺乏会导致肠道过度生长明显和肠道祖细胞的数量增加。我假设肠的增殖能力增加是由SREBP-1敲除中SREBP-1的补偿性刺激引起的。接下来，我发现肠道中SREBP-1的过表达再现了这种肠道过度生长，证实控制脂肪酸合成的SREBP-1是肠上皮生长的关键调节剂。该建议的目的是确定SREBPS控制肠上皮增殖的分子机制。中心假设是，SREBP通过产生维持肠道祖细胞增殖的脂质代谢产物来维持肠上皮的稳态。因此，将追求以下特定目标：（1）确定SREBP-1如何驱动肠上皮的生长。（2）确定srebps介导其对肠道生长的影响的细胞室。（3）使用无偏的转录组和脂质组分析，以鉴定脂质代谢产物及其生物合成酶，这些酶是SREBPS对上皮的影响的基础。这些目标将通过使用CRE-LoxP工具的新型小鼠模型来实现，以调节体内肠道，RNA-SEQ和脂肪组学测量值以及肠癌的基因和标记表达，以用于体外机械实验。该提案的预期结果是鉴定SREBP调节肠道生长的机制。这种结果将产生积极的翻译影响，因为可行的是，新鉴定的脂质调节剂将代表可以通过药理操作的新型治疗靶标。在肠癌的情况下，可以抑制生长刺激，以抗癌作用或在短肠的情况下刺激。最后，对肠道中肠道脂质代谢的更好理解将有助于开发肥胖症的新疗法，例如NAFLD，这在美国是流行病