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、微生物和饮食的主要部位。 因素相互作用。这种多系统相互作用严格调节全身生理机能 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。作为曝光量最大的企业之一 在身体表面，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道干细胞补充，以维持肠道稳态和 功能。因此，破译肠道稳态的调节机制是 对于了解正常肠道功能以及胃肠道疾病很重要 包括结直肠癌。尽管控制肠道稳态的基因程序 已被广泛研究，但人们对机械力如何—— 肠道蠕动和食物通过产生的物质可以调节肠道干细胞 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 剖析剪切应力作为肠腔的自然力如何调节肠道 稳态和肠道稳态​​。我们的试点研究取得了新的发现 剪切应力通过 Ca2+ 通道激活肠内分泌细胞中的 Ca2+ 信号 色氨酸A1。此外，TrpA1 的破坏显着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）剪切应力调节肠道 通过 TrpA1 依赖性 EE 激活和随后释放 来自 EE 的信号分子，2) 剪切应力通过调节 TrpA1 来激活 细胞膜的固有特性。在这个合作项目中，我们计划测试这些 通过利用果蝇遗传学的力量并将其与新的假设相结合 力学生物学分析和干细胞生物学。因为 TrpA1 表达为 哺乳动物的 EE，并且因为我们发现哺乳动物的 TrpA1 也被剪切激活 压力，我们提出的研究可能会对肠道生理学产生广泛的影响，包括 哺乳动物的。