Directing Cell Fate Along the Intestinal Enteroendocrine Lineage

沿着肠肠内分泌谱系引导细胞命运

• 批准号: 10002751
• 负责人: Kelley Yan
• 金额: $ 243万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10002751
• 关键词: Appetite Stimulants; Body Weight; Cell Lineage; Cells; Complex; Desire for food; Diabetes Mellitus; Disease; Eating; Endocrine Glands; Energy Metabolism; Enteroendocrine Cell; Epithelial; Epithelium; Functional disorder; Gastrointestinal tract structure; Goals; Hormonal; Hormones; Hunger; Intestines; Knowledge; Neuraxis; Obesity; Output; Pathogenesis; Pathway interactions; Patients; Pharmacology; Production; Proliferating; Public Health; Resolution; Satiation; System; Therapeutic; Tissues; Translations; comorbidity; energy balance; high reward; high risk; hormonal signals; human disease; in vivo; insight; intestinal crypt; intestinal epithelium; novel; obesity treatment; self-renewal; stem; stem cell differentiation; stem cells

Project Summary/Abstract Body weight and energy balance are tightly regulated by complex hormonal interplay of the gut and the central nervous system to control appetite and energy expenditure. Gut hormone signals from intestinal enteroendocrine cells (EECs) can either be orexigenic, enhancing hunger and promoting food intake, or anorexigenic, promoting satiety to inhibit food intake. Gut hormonal signaling dysfunction is implicated in obesity, a disease with enormous public health burden in the US and worldwide. Understanding this dysfunction will provide critical insight to the pathogenesis of obesity and its co-morbidities, and ultimately provide novel avenues to ameliorate it. The gastrointestinal tract is the largest endocrine organ and harbors the greatest number of hormone- producing cells in the body. This system holds vast potential for our ability to understand, and possibly manipulate, hormone signaling dysfunction. However, our understanding of hormones and the EECs that produce them remain poor. The intestinal epithelium is a rapidly self-renewing tissue and contains rare, heterogeneous EECs scattered throughout that produce a variety of hormones. EECs are generated from the sequential differentiation of multi-potent actively proliferating intestinal stem cells residing in the intestinal crypts that continuously produce replacement cells to support cellular turnover of the epithelium. The evolving understanding of cellular lineage hierarchy upon intestinal stem cell differentiation suggest that, rather than exogenous hormone delivery to patients, we may be able to pharmacologically manipulate the intestinal stem/progenitor cell state to guide their in vivo lineage output toward production of distinct EEC subtypes or to control the release of their hormone products for therapeutic applications. Here we will define the intestinal EEC lineage at single-cell resolution, including its diverse and discrete subtypes, and study how they are inter-related, to exponentially advance existing knowledge of these cells. We will also identify and functionally dissect the pathways that enforce specific EEC subtypes that would be therapeutically beneficial. This a high-risk/high-reward proposal with potential for direct translation to treatment of obesity and diabetes, which are global-scale human diseases.

项目概要/摘要 体重和能量平衡受到肠道和中枢神经系统复杂的激素相互作用的严格调节。 神经系统控制食欲和能量消耗。来自肠道内分泌的肠道激素信号 细胞（EEC）可以是引起食欲的，增强饥饿感并促进食物摄入，也可以是厌食的，促进 饱腹感抑制食物摄入。肠道激素信号传导功能障碍与肥胖有关，肥胖是一种影响巨大的疾病 美国和全世界的公共卫生负担。了解这种功能障碍将为我们提供重要的见解 肥胖及其并发症的发病机制，并最终提供改善肥胖的新途径。 胃肠道是最大的内分泌器官，含有最多的激素 体内产生细胞。这个系统对于我们理解并可能操纵的能力具有巨大的潜力 激素信号传导功能障碍。然而，我们对激素和产生激素的 EEC 的了解 仍然贫穷。肠上皮是一种快速自我更新的组织，含有稀有的异质 EEC 散布各处，产生各种激素。 EEC 是由顺序分化产生的 驻留在肠隐窝中的多能活跃增殖的肠干细胞不断产生 替代细胞支持上皮细胞的更新。对细胞谱系不断发展的理解 肠道干细胞分化的等级表明，而不是外源激素递送 对于患者，我们也许能够通过药理学手段操纵肠道干/祖细胞状态来指导他们 体内谱系输出用于产生不同的 EEC 亚型或控制其激素的释放 用于治疗应用的产品。在这里，我们将以单细胞分辨率定义肠道 EEC 谱系， 包括其多样化和离散的亚型，并研究它们如何相互关联，以指数方式推进 这些细胞的现有知识。我们还将识别并从功能上剖析执行特定的途径 对治疗有益的 EEC 亚型。这是一个高风险/高回报的提案，有潜力 直接转化为治疗肥胖和糖尿病这两种全球范围的人类疾病。