Defining GATA4’s Molecular Function in Gastric Cell Biology

定义 GATA4 在胃细胞生物学中的分子功能

• 批准号: 10536433
• 负责人: MICHELE A BATTLE
• 金额: $ 53.57万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536433
• 关键词: Acids; Address; Affect; Atrophic; Automobile Driving; Back; Binding; Biology; Cancer Etiology; Cell Differentiation process; Cell Lineage; Cell physiology; Cellular biology; Cessation of life; Chemicals; Chief Cell; Chronic Gastritis; Data; Development; Diagnosis; Digestion; Disease; Enhancers; Epithelial; Epithelial Cells; Foundations; Functional disorder; Future; GATA4 gene; Gastric Acid; Gastric Glands; Gastric Parietal Cells; Gastric Tissue; Gastritis; Gene Expression; Genes; Genetic Transcription; Goals; Growth Factor; Health; Helicobacter Infections; Helicobacter pylori; Homeostasis; Human; Hypermethylation; Infection; Injury; Knock-in; Knowledge; Light; Malignant Neoplasms; Metaplasia; Modeling; Molecular; Morphology; Mus; Natural regeneration; Nucleic Acid Regulatory Sequences; Organoids; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Peptic Ulcer; Persons; Pharmaceutical Preparations; Phenotype; Play; Promoter Regions; Proteomics; Rodent; Role; Stomach; Stomach Diseases; Testing; Ulcer; cell type; clinical application; experience; gastric organoids; genome-wide; human disease; insight; interest; malignant stomach neoplasm; mouse model; novel; overexpression; programs; promoter; socioeconomics; tool; transgene expression

SUMMARY Gastric parietal cells (PCs) play a critical role in GI function by secreting acid for digestion and protection against infection and by synthesizing growth factors that influence the development of other cell types including zymogenic chief cells. Although there has been longstanding interest in defining PC biology and gastric acid secretion dating back to the 1800s, PCs have been challenging to study. PC dysfunction, including acid hypersecretion or hyposecretion, underlies a range of human diseases associated with a high socioeconomic burden including chronic gastritis, drug-related peptic ulcer disease, Helicobacter pylori related peptic ulcer disease, and cancer. For example, peptic ulcer disease affects more than 4 million people in the US each year with 1 in 10 persons experiencing an ulcer at least once, and gastric cancer is the third leading cause of cancer related deaths worldwide. Given the essential role for PCs in maintaining a healthy stomach, it is surprising that a comprehensive understanding of the molecular programs that regulate and maintain normal PC differentiation and function, and thereby PC health and overall gastric epithelial cell health, is incomplete. Our finding that the transcription factor GATA4 binds to the regulatory regions—enhancers and promoters—of 81% of gene set defined as being uniquely expressed in PCs sheds light on the PC knowledge gap, implicating GATA4 as a crucial principal regulator of PC biology. The goal of this proposal is to test the central hypothesis that GATA4 is required to maintain homeostasis of the mature gastric epithelium by directly controlling the gene expression program defining PC function. Studies in Aim 1 will define the mechanistic contribution of GATA4 to PC function using a conditional mouse model to delete GATA4 in PCs and a suite of morphological and molecular investigative tools. Studies in Aim 2, using a Gata4 conditional knock-in model uniquely available in our lab to overexpress GATA4 in PCs in conjunction with gastric injury, will provide evidence to determine the extent to which GATA4 loss is necessary for PC dysfunction and downstream metaplasia. We will also examine the contribution of GATA4 promoter hypermethylation to PC dysfunction and metaplasia. Finally, studies in Aim 3 will apply findings from the mouse to human PC biology using human gastric organoids to determine the extent to which GATA4 function in PCs is evolutionarily conserved. Overall, we expect our studies to elucidate GATA4-dependent molecular pathways essential to maintain PC function and health and that, when disrupted, cause PC dysfunction and gastric disease. Discoveries of fundamental cellular and molecular mechanisms, in this case those underpinning normal gastric epithelial cell homeostasis, can provide prerequisite knowledge to apply to future clinical applications for gastric diseases including gastritis, peptic ulcer disease, metaplasia, and cancer.

概括 胃壁细胞 (PC) 通过分泌酸进行消化和保护，在胃肠道功能中发挥着关键作用 抵抗感染并合成影响其他细胞类型发育的生长因子，包括 酶原主细胞。尽管人们长期以来对 PC 生物学和胃酸的定义感兴趣 PC 的分泌可以追溯到 1800 年代，研究 PC 一直具有挑战性。 PC 功能障碍，包括胃酸 分泌过多或分泌不足是一系列与高社会经济相关的人类疾病的基础 负担包括慢性胃炎、药物相关消化性溃疡病、幽门螺杆菌相关消化性溃疡 疾病和癌症。例如，美国每年有超过 400 万人受到消化性溃疡病的影响 十分之一的人至少经历过一次溃疡，而胃癌是癌症的第三大原因 全球相关死亡事件。鉴于电脑在维持胃健康方面的重要作用，令人惊讶的是 全面了解调节和维持正常 PC 的分子程序 分化和功能，以及 PC 健康和整体胃上皮细胞健康，都是不完整的。我们的 发现转录因子 GATA4 与调节区域（增强子和启动子）结合 81% 的基因组被定义为在 PC 中独特表达，揭示了 PC 知识差距， 表明 GATA4 是 PC 生物学的重要主要调节因子。该提案的目标是测试 中心假设是 GATA4 是维持成熟胃上皮稳态所必需的 直接控制定义PC功能的基因表达程序。目标 1 的研究将定义 使用条件小鼠模型删除 PC 中的 GATA4，研究 GATA4 对 PC 功能的机制贡献 以及一套形态学和分子研究工具。目标 2 中的研究，使用 Gata4 条件 我们实验室独有的敲入模型可在 PC 中过度表达 GATA4 并导致胃损伤， 将提供证据来确定 GATA4 缺失对于 PC 功能障碍的必要程度，以及 下游化生。我们还将研究 GATA4 启动子高甲基化对 PC 的贡献 功能障碍和化生。最后，Aim 3 的研究将把小鼠的研究结果应用到人类 PC 生物学中 使用人类胃类器官来确定 PC 中 GATA4 功能的进化程度 保守的。总的来说，我们希望我们的研究能够阐明 GATA4 依赖性分子途径，这对于 维持 PC 功能和健康，如果受到干扰，会导致 PC 功能障碍和胃病。 基本细胞和分子机制的发现，在本例中是支撑正常胃的机制 上皮细胞稳态，可以为未来的临床应用提供必要的知识 胃病包括胃炎、消化性溃疡、化生和癌症。