Directing Cell Fate Along the Intestinal Enteroendocrine Lineage

项目摘要/摘要 体重和能量平衡受到肠道和中枢复杂荷尔蒙相互作用的严格调节。 神经系统控制食欲和能量消耗。来自肠道内分泌的胃肠激素信号 细胞(EECs)既可以是食欲旺盛、促进饥饿和促进食物摄取的细胞，也可以是厌食、促进食物摄入的细胞。 饱腹感抑制食物摄取。肠道激素信号功能障碍与肥胖有关，这是一种具有巨大 美国和世界范围内的公共卫生负担。了解这种功能障碍将为 肥胖及其共病的发病机制，并最终提供了新的途径来改善它。 胃肠道是最大的内分泌器官，含有最多的激素- 在体内产生细胞。这个系统拥有巨大的潜力，使我们能够理解，并可能操纵， 激素信号功能障碍。然而，我们对荷尔蒙和产生荷尔蒙的EECS的理解 继续保持贫穷。肠上皮是一种快速自我更新的组织，含有稀有的异种上皮细胞。 分散在各处会产生各种荷尔蒙。EEC是从顺序分化中产生的 驻留在肠道隐窝中的多潜能活跃增殖的肠道干细胞 替代细胞以支持上皮细胞的周转。对细胞谱系的发展认识 肠道干细胞分化的层级表明，而不是外源性激素输送到 患者，我们可能能够从药物上操纵肠道干细胞/祖细胞状态，以引导他们的 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，我们将定义单细胞分辨率的肠道内皮细胞谱系， 包括其多样和离散的亚型，并研究它们是如何相互关联的，以指数级的方式前进 对这些细胞的现有知识。我们还将确定并从功能上剖析强制执行特定 对治疗有益的EEC亚型。这是一个高风险/高回报的提议，具有潜在的 直接翻译为肥胖和糖尿病的治疗，这两种疾病是全球范围的人类疾病。

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.