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.

项目描述 肠道上皮是神经、免疫、微生物和饮食系统的主要场所， 因素相互作用。这种多系统相互作用严格地调节全身生理学 包括代谢、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。作为世界上最大的 在人体的各个表面，每天有数十亿个细胞从人体肠道上皮脱落。 这些丢失的细胞由肠干细胞补充以维持肠道内稳态， 功能协调发展的因此，解读肠道内稳态的调节机制是 对于理解正常的肠道功能以及胃肠疾病很重要 包括结肠直肠癌虽然控制肠道内稳态的基因程序 已经被广泛研究过了，但对机械力是如何作用的却知之甚少 肠干细胞在肠道蠕动和食物传递过程中的作用 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， 分析切应力作为肠腔的自然力， 内稳态和肠道内稳态。我们的试点研究有了新的发现， 切应力通过Ca2+通道激活肠内分泌细胞中的Ca2+信号 TrpA1。此外，TrpA1的破坏显着降低肠干细胞增殖。 基于这些令人兴奋的结果，我们假设：1）切应力调节肠道 通过TrpA1依赖性激活EE和随后释放 2）剪切应力通过调节细胞内的信号分子来激活TrpA1， 细胞膜固有特性。在这个合作项目中，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 因为我们发现哺乳动物的TrpA1也被剪切激活， 我们提出的研究可能会对肠道生理学产生广泛的影响， 这是哺乳动物。