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 胃顶细胞（PC）通过分泌酸消化和保护在GI功能中起关键作用 反对感染和通过影响影响其他细胞类型的发展的生长因素，包括 酶促的主要细胞。尽管对定义PC生物学和胃酸一直很感兴趣 分泌可以追溯到1800年代，PC是研究的挑战。 PC功能障碍，包括酸 过度分泌或分泌性，是一系列与高社会经济相关的人类疾病的基础 包括慢性胃炎，药物相关的消化性溃疡，幽门螺杆菌相关的消化性溃疡，包括慢性胃炎的负担 疾病和癌症。例如，消化性溃疡每年影响美国超过400万人 至少有十分之一的人至少经历一次溃疡，而胃癌是癌症的第三大主要原因 全球相关的死亡。考虑到PC在保持健康胃中的重要作用，这令人惊讶 对调节和维持正常PC的分子程序的全面了解 分化和功能，因此PC健康和整体胃皮细胞健康是不完整的。我们的 发现转录因子GATA4与调节区域（增强剂和启动子）结合 81％的基因集被定义为在PC中唯一表达的基因集在PC知识鸿沟上阐明 将GATA4植入PC生物学的关键主要调节剂。该提议的目的是测试 中心假设是，GATA4需要通过 直接控制定义PC函数的基因表达程序。 AIM 1的研究将定义 GATA4使用条件鼠标模型对PC函数的机械贡献来删除PC中的GATA4 以及一套形态和分子研究工具。在AIM 2中使用GATA4条件的研究 在我们的实验室中唯一可用的敲入模型可在PC中与胃损伤结合使用， 将提供证据以确定PC功能障碍需要的GATA4损失的程度 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中的研究将应用于小鼠的发现对人类PC生物学 使用人类胃癌来确定PC中GATA4在多大程度上是进化的 保守。总体而言，我们希望我们的研究能够阐明GATA4依赖性分子途径 保持PC功能和健康状况，并在中断时会引起PC功能障碍和胃病。 基本细胞和分子机制的发现，在这种情况下，基于正常胃的基础的发现 上皮细胞稳态，可以提供先决条件知识，以适用于将来的临床应用 胃炎，包括胃炎，胡椒溃疡，化生和癌症。