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.

项目概要 此次重新提交的新 R01 申请旨在定义胃干细胞调节机制， 研究 Wnt 信号传导在维持组织稳态和促进上皮细胞增殖中的作用 在胃里。我们提出的研究与人类疾病直接相关，重点关注疾病的机制 家族性腺瘤性息肉病（FAP）患者的胃息肉形成。 FAP是一种遗传性疾病 由种系 APC 基因突变导致 Wnt 信号传导失调，导致严重胃肠道 (GI) Wnt 促进干细胞增殖而导致的增殖性疾病。尽管 Wnt 众所周知 调节胃肠道干细胞，但关于胃肠道不同区域对 Wnt 失调的敏感性仍然存在疑问 道。 FAP 患者的结肠表现极为严重，其侵袭性疾病的特点是早期 腺瘤和癌症的发展，通常会导致年轻时进行结肠切除术。的后果 尽管息肉、腺瘤和癌症，但胃干细胞中的 Wnt 失调尚不清楚 FAP 患者胃部的发育得到增强。值得注意的是，几乎所有 FAP 患者都表现出频繁的 过度增殖性息肉局限于胃的近端胃底/胃体区域，而相反， 胃的远端胃窦/幽门区域相对不受这些息肉的影响，并且偶尔会出现 腺瘤生长。 FAP 突变对体干细胞和胃窦干细胞的区域影响的基础 胃组织反应尚不清楚。为了解决这个重要问题，该项目重点定义 Wnt 胃干细胞的调节以揭示近端与远端通路激活的差异效应 胃。我们将通过功能和遗传来探究胃中FAP息肉形成的机制。 对人类 FAP 胃组织生物库中的胃息肉和非息肉类器官和组织进行分析 将作为本研究的一部分构建的样本。人类 FAP 类器官研究将得到补充 小鼠遗传、药理学和类器官模型，以获得对区域 Wnt 更深入的机制了解 胃干细胞的调节。这些研究以“恰到好处的假设”为框架，该假设定义了 基于区域特异性干细胞对不同水平的反应的胃肠道的不同敏感性 Wnt 激活。拟议的研究将共同​​确定 Wnt 信号传导失调如何导致 近端胃与远端胃的胃上皮细胞增殖和息肉形成的差异。这 这些信息将建立一个科学框架来帮助定义 FAP 患者的胃部表现。在 此外，这些研究将提供功能见解，以加深对 Wnt 通路的理解 胃肠道干细胞的调节。此外，了解 Wnt 通路调节机制 胃干细胞功能对于完善在培养物中繁殖成体干细胞的策略非常重要 再生疗法以及制定胃病的诊断标准和潜在疗法 过度增殖性疾病。