Wnt Pathway Regulation of Gastric Stem Cell Function

胃干细胞功能的 Wnt 通路调控

• 批准号: 10557120
• 负责人: LINDA C. SAMUELSON
• 金额: $ 50.92万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557120
• 关键词: APC gene; APC mutation; Address; Affect; Age; Alleles; Antral; Cell Differentiation process; Cell Proliferation; Cells; Colectomy; Colon; Complement; Culture Media; Development; Disease; Distal; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Exhibits; Familial Adenomatous Polyposis Syndrome; Gastric Polyp; Gastric Tissue; Gastrointestinal tract structure; Gene Mutation; Genes; Genetic Diseases; Genetic Models; Growth; Homeostasis; Human; Hyperplasia; Individual; Induced Mutation; Knowledge; Maintenance; Malignant Neoplasms; Measures; Modeling; Molecular; Mus; Mutation; Organ; Organoids; Pathway interactions; Patients; Polyps; Pylorus; Regulation; Role; Signal Transduction; Stomach; Stomach Diseases; Testing; Tissue Expansion; Tissue Sample; Tissues; WNT Signaling Pathway; adenoma; adult stem cell; biobank; cell type; diagnostic criteria; gastric organoids; gastrointestinal; genetic analysis; human disease; human tissue; insight; mouse genetics; mutant; novel; patient response; pharmacologic; polyposis; regenerative therapy; response; self-renewal; stem; stem cell expansion; stem cell function; stem cell homeostasis; stem cell proliferation; stem cells; tumorigenesis

PROJECT SUMMARY This resubmission of a new R01 application proposes to define mechanisms of gastric stem cell regulation, investigating the role of Wnt signaling to maintain tissue homeostasis and to promote epithelial cell proliferation in the stomach. Our proposed studies are directly relevant to human disease, focusing on mechanisms of gastric polyp formation in patients with familial adenomatous polyposis (FAP). FAP is a genetic disorder resulting from germline APC gene mutations that dysregulate Wnt signaling, with extreme gastrointestinal (GI) proliferative disease resulting from Wnt promotion of stem cell proliferation. Although Wnt is well known to regulate GI stem cells, questions remain regarding sensitivity to Wnt dysregulation in different regions of the GI tract. Colonic manifestations in FAP patients are extreme, with aggressive disease characterized by early adenoma and cancer development, which commonly leads to colectomy at a young age. The consequences of Wnt dysregulation in gastric stem cells is less well understood, although polyp, adenoma and cancer development are enhanced in the FAP patient stomach. Notably, almost all FAP patients exhibit frequent hyperproliferative polyps localized to the proximal fundic/corpus region of the stomach, while, in contrast, the distal antral/pylorus region of the stomach is relatively spared from these polyps and develops more occasional adenomatous growths. The basis for the regional effect of FAP mutations on corpus vs. antral stem cells and gastric tissue responses is unknown. To address this important question, this project focuses on defining Wnt regulation of gastric stem cells to uncover the differential effects of pathway activation in the proximal vs. distal stomach. We will pursue the mechanisms of FAP polyp formation in the stomach by functional and genetic analysis of gastric polyp and non-polyp organoids and tissues from a biobank of human FAP gastric tissue samples that will be built as a component of this study. Human FAP organoid studies will be complemented by mouse genetic, pharmacologic and organoid models to gain deeper mechanistic insight into regional Wnt regulation of gastric stem cells. The studies are framed by the “Just Right Hypothesis” which defines differential sensitivities along the GI tract based on region-specific stem cell responses to different levels of Wnt activation. Together the proposed studies will determine how dysregulated Wnt signaling leads to differential gastric epithelial cell proliferation and polyp formation in proximal vs. distal stomach. This information will establish a scientific framework to help define the gastric manifestations in FAP patients. In addition, the studies will provide functional insights to develop a deeper understanding of Wnt pathway regulation of gastrointestinal stem cells. Furthermore, understanding mechanisms of Wnt pathway regulation of gastric stem cell function is important to refine strategies to propagate adult stem cells in culture for regenerative therapies as well as to develop diagnostic criteria and potential therapies for gastric hyperproliferative diseases.

项目总结 这项新的R01申请的重新提交提出了定义胃干细胞调节机制的建议， 探讨Wnt信号在维持组织动态平衡和促进上皮细胞增殖中的作用 在胃里。我们建议的研究与人类疾病直接相关，重点是 家族性腺瘤性息肉病(FAP)患者胃息肉的形成FAP是一种遗传性疾病 由生殖系APC基因突变导致的Wnt信号失调，并伴有极端胃肠道(GI) 由Wnt促进干细胞增殖引起的增殖性疾病。尽管WNT是众所周知的 调节GI干细胞，关于GI不同区域对Wnt异常的敏感性的问题仍然存在 一条小路。FAP患者的结肠表现极端，具有侵袭性疾病的特点是早期 腺瘤和癌症的发展，这通常会导致在年轻的时候进行结肠切除术。其后果是 尽管息肉、腺瘤和癌症，WNT在胃干细胞中的调节失调还不是很清楚 FAP患者胃部发育增强。值得注意的是，几乎所有的FAP患者都表现出 过度增生性息肉局限于胃底/胃体近端区域，而与之相反， 胃的远端胃窦/幽门区域相对不受这些息肉的影响，并且更偶尔发生。 腺瘤性生长。FAP突变对体部和胃窦干细胞的区域性影响的基础 胃组织的反应尚不清楚。为了解决这个重要的问题，本项目侧重于定义WNT 调节胃干细胞以揭示近端和远端通路激活的差异效应 胃。我们将从功能和遗传学方面探讨胃FAP息肉形成的机制。 人FAP胃组织生物库中胃息肉和非息肉组织的分析 将作为本研究的组成部分构建的样本。人类FAP有机体研究将得到以下补充 小鼠遗传、药理学和器官模型以更深入地了解区域WNT的机制 胃干细胞的调控。这些研究的框架是“恰到好处的假说”，它定义了 基于区域特异性干细胞对不同水平的 WNT激活。总之，拟议的研究将确定不受调控的Wnt信号如何导致 近端与远端胃上皮细胞增殖和息肉形成的差异。这 信息将建立一个科学框架，以帮助定义FAP患者的胃表现。在……里面 此外，这些研究将为深入理解Wnt途径提供功能洞察力 胃肠道干细胞的调控。此外，了解Wnt信号转导途径的调控机制 胃干细胞的功能对于改进成体干细胞在培养中繁殖的策略很重要 再生疗法以及制定胃病的诊断标准和潜在的治疗方法 增生性疾病。