Gastrin Regulation of Gastric Antral Stem and Corpus Progenitor Cells

胃窦干细胞和胃体祖细胞的胃泌素调节

基本信息

批准号：
10686228
负责人：
Timothy Cragin Wang
金额：
$ 49.9万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-23 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686228
关键词：
Ablation Acetic Acids Acids Agonist Antral Bacterial Artificial Chromosomes Behavior CCKBR gene Carcinogens Cell Count Cell Lineage Cell Proliferation Cell division Cells Cholecystokinin B Receptor Data Diphtheria Toxin Disease Endocrine Enterochromaffin Cells Enterochromaffin-like Cells Epithelial Cells Epithelium Exhibits G Cells G-Protein-Coupled Receptors Gastric Parietal Cells Gastrins Gene Expression Gland Growth Helicobacter Helicobacter Infections Hormonal Hormone secretion Hormones Human In Vitro Inflammation Injury Long-Term Effects Longevity Mediating Methylnitrosourea Natural regeneration Parietal Pathway interactions Peptic Ulcer Population Prevention Process Production Proliferating Publishing Pyloric antrum Regenerative response Regulation Role Signal Transduction Stomach Stomach Neoplasms Technology Time Transgenic Mice Ulcer bone carcinogenicity gastric tumorigenesis healing in vivo peptide hormone progenitor receptor regeneration following injury response response to injury self renewing cell single-cell RNA sequencing stem stem cell division stem cell proliferation stem cells stemness

项目摘要

Project Summary / Abstract The gastrin receptor, Cck2r, is a G-protein coupled receptor known to be expressed in the corpus in enterochromaffin-like (ECL) and parietal cells where it regulates acid secretion. However, it is also expressed in corpus progenitor cells and antral stem cells where it modulates their behavior in distinct ways. Recently, we have shown that Cck2r+ antral cells are self-renewing +4 stem cells that undergo predominant asymmetric cell division. However, in response to gastrin deficiency or carcinogenic injury, these antral stem cells shift to symmetric cell division and lineage trace more rapidly, indicating that gastrin acts to regulate Cck2r+ antral cell proliferation, and suggesting that antral G cells are niche cells. In contrast, we have shown that Cck2r+ corpus isthmal cells are ECL cell progenitors that respond to hypergastrinemia, which acts in a hormonal fashion to increase their proliferation and tracing, producing more ECL cells. Thus, we propose to study these two distinct Cck2r-expressing stomach progenitor cells and dissect more deeply their responses to gastrin stimulation through the following two Aims: Aim #1. What is the role of gastrin signaling in antral +4 stem cells? We will investigate the role of gastrin, both in vitro and in vivo, in modulating Cck2r+ antral stem cell responses to the major niche signals, R-spondin and Wnt, using adenovirally delivered agonists, and then validate antral gastrin (G) cells as true niche cells through targeted DTR ablation. We will investigate the response of Cck2r+ antral cells to both gastrin and carcinogens (MNU) using single cell RNA-sequencing. Aim #2. What is the role of gastrin signaling in corpus ECL cell progenitors? We propose to study the effects of long-term hypergastrinemia on Cck2r+ corpus progenitors, and also investigate the role of these isthmal progenitors in the response to corpus inflammation (H. pylori infection) and ulceration (acetic acid injury) with or without hypergastrinemia. Finally, we propose to characterize Cck2r+ corpus progenitors and their response to gastrin using single cell RNA-seq, in order to understand how gastrin may modulate the plasticity and longevity of corpus progenitors. Overall, these studies will seek to leverage the latest technologies to advance our understanding of the role of gastrin in modulating growth and regeneration of the stomach.

项目概要/摘要胃泌素受体 Cck2r 是一种 G 蛋白偶联受体，已知在体内表达肠嗜铬样 (ECL) 和壁细胞，调节酸分泌。然而，它也表达为体祖细胞和窦干细胞以不同的方式调节它们的行为。最近，我们已表明 Cck2r+ 窦细胞是自我更新的 +4 干细胞，经历主要的不对称细胞分配。然而，为了应对胃泌素缺乏或致癌损伤，这些胃窦干细胞会转变为对称细胞分裂和谱系追踪更快，表明胃泌素可调节 Cck2r+ 胃窦细胞增殖，并表明窦 G 细胞是生态位细胞。相比之下，我们已经证明 Cck2r+ 语料库峡部细胞是对高胃泌素血症作出反应的 ECL 细胞祖细胞，高胃泌素血症以激素方式发挥作用增加它们的增殖和追踪，产生更多的 ECL 细胞。因此，我们建议研究这两种不同的表达 Cck2r 的胃祖细胞并更深入地剖析它们对胃泌素刺激的反应通过以下两个目标：目标#1。胃泌素信号传导在胃窦+4干细胞中的作用是什么？我们将研究胃泌素在体外和体内调节 Cck2r+ 胃窦干细胞对使用腺病毒传递的激动剂检测主要生态位信号 R-spondin 和 Wnt，然后验证胃泌素 (G) 通过定向 DTR 消融将细胞视为真正的利基细胞。我们将研究 Cck2r+ 窦的反应使用单细胞 RNA 测序检测细胞对胃泌素和致癌物 (MNU) 的影响。目标#2。的作用是什么胃泌素信号传导在体 ECL 细胞祖细胞中？我们建议研究长期高胃泌素血症的影响对 Cck2r+ 语料库祖细胞进行研究，并研究这些峡部祖细胞在语料库反应中的作用炎症（幽门螺杆菌感染）和溃疡（醋酸损伤），伴或不伴高胃泌素血症。最后，我们建议使用单细胞 RNA-seq 来表征 Cck2r+ 语料库祖细胞及其对胃泌素的反应，为了了解胃泌素如何调节体祖细胞的可塑性和寿命。总体而言，这些研究将寻求利用最新技术来加深我们对胃泌素在调节胃的生长和再生。