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

• 批准号: 10367556
• 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
• 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/10367556
• 关键词: Ablation; Acetic Acids; Acids; Address; Agonist; Antral; Bacterial Artificial Chromosomes; Behavior; CCKBR gene; Carcinogens; Cell Count; Cell Lineage; Cell Proliferation; Cell division; Cells; Cholecystokinin B Receptor; Coupled; Data; Diphtheria Toxin; Disease; Endocrine; Enterochromaffin Cells; Enterochromaffin-like Cells; Epithelial; Epithelial Cells; Exhibits; G Cells; Gastric Parietal Cells; Gastrins; Gene Expression; Gland; Growth; Helicobacter; Helicobacter Infections; Hormonal; Hormones; Human; In Vitro; Inflammation; Injury; Long-Term Effects; Longevity; Mediating; Methylnitrosourea; Natural regeneration; Parietal; Pathway interactions; Peptic Ulcer; Population; Prevention; Process; Production; Proteins; Publishing; Pyloric antrum; Regenerative response; Regulation; Role; S-Phase Fraction; 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

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.

项目总结/摘要 胃泌素受体，Cck2r，是一种G蛋白偶联受体，已知在胃肠道的胃体中表达。 肠嗜铬样细胞（ECL）和壁细胞，它调节酸分泌。然而，它也表现在 体祖细胞和胃窦干细胞，它以不同的方式调节它们的行为。最近我们 已经表明，Cck2r+胃窦细胞是自我更新的+4干细胞，其经历主要的不对称细胞分化， 师.然而，作为对胃泌素缺乏或致癌性损伤的反应，这些胃窦干细胞转移到 对称细胞分裂和谱系追踪更快，表明胃泌素起调节Cck 2r+胃窦细胞作用 提示胃窦G细胞为小生境细胞。相比之下，我们已经表明，Cck2r+语料库 峡部细胞是响应高胃泌素血症的ECL细胞祖细胞，高胃泌素血症以激素方式起作用， 增加它们的增殖和示踪，产生更多的ECL细胞。因此，我们建议研究这两个不同的 表达cck 2r的胃祖细胞，并更深入地剖析它们对胃泌素刺激的反应 有两个目标：目标#1。胃泌素信号在胃窦+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Cck 2r+胃窦干细胞对Cck 2r+胃窦干细胞的反应中的作用。 主要的生态位信号，R-spondin和Wnt，使用腺病毒递送的激动剂，然后验证胃窦胃泌素 (G)通过靶向DTR消融将细胞作为真正的小生境细胞。我们将研究CCK 2r+胃窦的反应， 细胞对胃泌素和致癌物（MNU）的作用。目标2。的作用是什么 胃泌素信号在ECL体细胞祖细胞中的作用我们建议研究长期高胃泌素血症的影响 对Cck2r+体祖细胞的影响，并研究这些峡部祖细胞在对体的反应中的作用。 炎症（H.幽门螺杆菌感染）和溃疡（乙酸损伤）伴或不伴高胃泌素血症。最后我们 建议使用单细胞RNA-seq表征Cck2r+体祖细胞及其对胃泌素的反应， 以了解胃泌素如何调节体祖细胞的可塑性和寿命。总的来说，这些 研究将寻求利用最新的技术来促进我们对胃泌素在 调节胃的生长和再生。