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

基本信息

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
项目类别：
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

项目摘要

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。这种多系统互动严格调节全身生理包括代谢，免疫学和神经退行性疾病。基于此相互作用是健康且平衡的肠道上皮。作为最大的暴露之一人体表面，每天从人类肠道上皮中脱落数十亿个细胞。这些丢失的细胞被肠干细胞取代，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理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遗传程序已经广泛研究了，关于机械力– – – – 由肠蠕动和食物传递产生的可能会调节肠干细胞行为。在这里，我们将成人果蝇中肠作为一个简单但强大的系统剖析剪切应力如何作为肠腔的自然力可以调节肠道稳态和肠内稳态。我们的飞行员研究提出了新发现的结果剪切应力通过Ca2+通道激活肠内分泌细胞中的Ca2+信号 TRPA1。此外，TRPA1的破坏显着降低了肠道干细胞增殖。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EES的激活和随后释放的稳态来自EES的信号分子2）剪切应力通过调节激活TRPA1 细胞膜的内在特性。在这个协作项目中，我们计划测试这些假设通过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EES，并且因为我们发现哺乳动物TRPA1也被剪切激活压力，我们拟议的研究可能会对肠道生理产生广泛的影响，包括哺乳动物。