Mechanical regulation of intestine stem cell-mediated tissue homeostasis in Drosophila

果蝇肠干细胞介导的组织稳态的机械调节

• 批准号: 10638341
• 负责人: Yang Xiang
• 金额: $ 36.85万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638341
• 关键词: Adenosine; Adult; Biochemical; Biological; Biological Assay; Body Surface; Cell Count; Cell membrane; Cell physiology; Cells; Chemicals; Cognition; Colorectal Cancer; Cues; Defect; Detection; Dietary Factors; Disease; Drosophila genus; Electrophysiology (science); Enterocytes; Enteroendocrine Cell; Epithelial Cells; Epithelium; Exposure to; Food; Foundations; Gastrointestinal Diseases; Gastrointestinal tract structure; Generations; Genetic; Goals; Health; Homeostasis; Human; Image; Immune; Immunity; Impairment; Intestines; Irritants; Knock-in; Knowledge; Lipids; Liquid substance; Malignant neoplasm of gastrointestinal tract; Mammals; Mechanics; Mediating; Membrane; Membrane Fluidity; Metabolism; Midgut; Neurodegenerative Disorders; Neurons; Peristalsis; Physiological; Physiology; Pilot Projects; Property; Protein Isoforms; Purinergic P1 Receptors; Purines; Purinoceptor; Regulation; Reporting; Role; Shapes; Signal Transduction; Signaling Molecule; Site; Stimulus; Stretching; System; TRP channel; TRPA channel; Tachykinin; Testing; Time; Tissues; biological adaptation to stress; cell behavior; cell type; fly; gastrointestinal epithelium; gastrointestinal function; gut homeostasis; in vivo; innovation; mechanical force; mechanical signal; mechanotransduction; microbial; mutant; neural; novel; nutrient absorption; programs; public health relevance; receptor; response; selective expression; sensor; sensory stimulus; shear stress; stem cell biology; stem cell proliferation; stem cells; synergism; tissue regeneration; tool; tumorigenesis

Project description Gut epithelium is the principal site in which neural, immune, microbial and dietary factors interact. This multi-system interaction critically regulates whole-body physiology including metabolism, immunity, and neurodegenerative diseases. At the basis of this interaction is the healthy and balanced gut epithelium. As one of largest exposed surfaces of the body, billions of cells are shed from the human gut epithelium every day. These lost cells are replenished by intestine stem cells to maintain gut homeostasis and functions. Deciphering the regulatory mechanisms of gut homeostasis is therefore important for understanding normal gut functions as well as gastrointestinal disorders including colorectal cancer. Although genetic programs that control gut homeostasis have been extensively studied, very little is known about how mechanical forces–– generated by gut peristalsis and food passing could regulate intestine stem cell behavior. Here, we use the adult Drosophila midgut as a simple but robust system to dissect how shear stress as a natural force of the gut lumen could regulate gut homeostasis and gut homeostasis. Our pilot studies have made novel findings that shear stress activates Ca2+ signals in enteroendocrine cells through the Ca2+ channel TrpA1. Moreover, disruption of TrpA1 markedly reduced intestine stem cell proliferation. Based on these exciting results, we hypothesize that: 1) shear stress regulates gut homeostasis through TrpA1-dependent activation of EEs and subsequent release of signaling molecules from EEs, 2) shear stress activates TrpA1 by regulation of the intrinsic property of cell membrane. In this collaborative project, we plan to test these hypotheses by leveraging the power of Drosophila genetics and combining it with new mechanobiological analysis and stem cell biology. Because TrpA1 is expressed in mammalian EEs, and because we find that mammalian TrpA1 is also activated by shear stress, our proposed studies will likely have a broad impact in gut physiology including that of mammals.

项目说明 肠道上皮是神经、免疫、微生物和饮食的主要场所。 各种因素相互作用。这种多系统的相互作用对全身生理学起着至关重要的调节作用。 包括新陈代谢、免疫和神经退行性疾病。在此基础上 相互作用是健康和平衡的肠道上皮。作为最大的风险暴露之一 在人体的表面，每天有数十亿个细胞从人体的肠道上皮脱落。 这些丢失的细胞由肠道干细胞补充，以维持肠道内环境平衡和 功能。因此，破译肠道内稳态的调节机制是 对了解正常的肠道功能和胃肠功能障碍很重要 包括结直肠癌。尽管控制肠道动态平衡的遗传程序 已经得到了广泛的研究，关于机械力是如何-- 肠道蠕动和食物传递所产生的对肠道干细胞的调节作用 行为。在这里，我们使用成年果蝇中肠作为一个简单但强大的系统来 解剖作为肠腔自然力的切应力如何调节肠道 动态平衡和肠道动态平衡。我们的初步研究取得了新的发现， 切应力通过钙通道激活肠内分泌细胞内的钙信号 TRPA1.此外，破坏TRPA1显著降低了肠干细胞的增殖。 基于这些令人兴奋的结果，我们假设：1)剪切力调节肠道 通过依赖TRPA1激活EES并随后释放 来自EES的信号分子，2)剪切力通过调节 细胞膜的固有属性。在这个协作项目中，我们计划测试这些 利用果蝇遗传学的力量并将其与新的 机械生物学分析和干细胞生物学。因为TRPA1在 哺乳动物的EES，因为我们发现哺乳动物的TRPA1也被剪切力激活 压力，我们提议的研究可能会对肠道生理学产生广泛的影响，包括 就像哺乳动物一样。