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.

项目摘要 重新提出新的R01应用程序建议，以定义胃干细胞调节机制， 研究WNT信号传导维持组织稳态的作用并促进上皮细胞增殖 在对峙中。我们提出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）患者的胃息肉形成。 FAP是一种遗传疾病 由生殖线APC基因突变导致Wnt信号失调，具有极端胃肠道（GI） Wnt促进干细胞增殖引起的增殖疾病。虽然Wnt是众所周知的 调节GI干细胞，关于GI不同区域中Wnt失调的敏感性仍然存在问题 道。 FAP患者的结肠表现极为极端，其侵略性疾病的特征是早期 腺瘤和癌症发育，通常会导致年轻时的收集。后果 胃部干细胞中的Wnt失调尚不清楚，尽管息肉，腺瘤和癌症 FAP患者胃的发育增强。值得注意的是，几乎所有FAP患者暴露了频率 高增殖蛋白息肉位于胃的近端/语料库区域，相反， 胃的远端/幽门区域相对从这些息肉和发展中宽恕，而偶尔会偶尔 腺瘤生长。 FAP突变对语料库与肛门干细胞的区域效应的基础 胃组织反应尚不清楚。为了解决这个重要的问题，该项目着重于定义Wnt 调节胃干细胞以发现近端与不同的途径激活的差异作用 胃。我们将通过功能和遗传来追求Standmach中FAP息肉形成的机制 分析人类FAP胃组织的生物库的胃息肉和非圆柱体和组织 将作为本研究的组成部分构建的样品。人类FAP器官研究将由 小鼠遗传，药理学和器官模型，以获得更深入的机械洞察力洞察区域Wnt 调节胃干细胞。这些研究由定义的“正当假设”构建 基于区域特异性干细胞对不同水平的干细胞反应的差异敏感性 Wnt激活。共同提出的研究将确定Wnt信号失调如何导致 近端与胃部近端抗胃上皮细胞增殖和息肉形成。这 信息将建立一个科学框架，以帮助定义FAP患者的胃表现。 此外，研究将提供功能见解，以提高对Wnt途径的更深入的了解 调节胃肠道干细胞。此外，了解Wnt途径调节机制 胃干细胞功能对于完善在培养中传播成年干细胞的策略很重要 再生疗法以及制定胃的诊断标准和潜在疗法 过度增殖疾病。