Understanding the effects of sleep deprivation on the gut's cellular homeostatic process

了解睡眠不足对肠道细胞稳态过程的影响

• 批准号: 10679154
• 负责人: Alejandra Sofia Laureano Ruiz
• 金额: $ 6.95万
• 依托单位: HARVARD MEDICAL SCHOOL
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679154
• 关键词: Acute; Address; Affect; American; Animals; Back; Binding; Biological; Biological Models; Brain; Cardiometabolic Disease; Cardiovascular Diseases; Cause of Death; Cell Differentiation process; Cell secretion; Cells; Cessation of life; Chronic; Communication; Compensation; Complex; Data; Disease; Drosophila genus; Enteroendocrine Cell; Event; Fellowship; Functional disorder; Future; Genetic; Goals; Health; Homeostasis; Immunofluorescence Immunologic; Individual; Intestinal Diseases; Intestines; Knowledge; Lead; Long-Term Effects; Longevity; Mammals; Mentors; Modeling; Molecular; Molecular Profiling; Neurobiology; Organ; Oxidative Stress; Pathway interactions; Peptides; Physiology; Population; Process; Proliferating; Reactive Oxygen Species; Recovery; Regenerative capacity; Reporter; Research; Risk; Role; Secretory Cell; Sensory; Signal Pathway; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Technical Expertise; Testing; Work; cell growth; daughter cell; experimental study; fly; gastrointestinal epithelium; high risk; knock-down; negative affect; nutrient absorption; nutrition; poor sleep; premature; programs; response; severe injury; sleep behavior; sleep quality; sleep quantity; stem cell proliferation; stem cells; tool; tumor growth

Project Summary Individuals that suffer from chronic sleep disturbances are at high risk of developing intestinal dysfunction, which can promote acute cardiovascular and cardiometabolic diseases. My lab recently discovered that sleep and the gut have a bidirectional relationship. They found that the gut is specifically and critically injured during chronic sleep loss: sleep suppression causes the accumulation of reactive oxygen species (ROS) in this organ, which in turn causes oxidative stress and premature death of animals. The lab also uncovered a gut-to-brain peptidergic signaling pathway that regulates sleep depth. It is critical to determine how low sleep amount and poor sleep quality negatively impact the gut's physiology and function. I will use fruit flies as a model system to study the fundamental molecular, cellular, and functional relationship between sleep and the gut. My study will test the hypothesis that sleep loss results in an altered gut cellular composition that promotes increased sleep depth during recovery from sleep loss. The first aim of the proposal will focus on determining changes to gut cell composition in chronically sleep-deprived flies. I propose that sleep loss promotes intestinal stem cell proliferation and biases daughter cells toward enteroendocrine cell fate (gut sensory and secretory cells). I will combine immunofluorescence and fluorescent reporters to determine changes in intestinal stem cell proliferation and enteroendocrine cell fate determination. The second aim will examine sleep quality and lifespan in flies recovering from chronic sleep loss. I propose that changes in the gut cellular composition resulting from chronic sleep loss promote deeper sleep in flies recovering from sleep loss as a way to compensate for insufficient sleep. I will quantify the depth of sleep in chronically sleep-deprived flies throughout their lifespan and perform functional experiments to assess if peptides secreted by the enteroendocrine cells are responsible for increasing the depth of sleep during recovery. I will also functionally determine the contribution of these enteroendocrine cell-secreted peptides to the longevity of flies recovering from chronic sleep loss. Defining how cellular changes in the gut can impact the function of this organ and its role in regulating sleep will be fundamental for understanding the bidirectional sleep-gut relationship. More generally, this work will contribute to understanding how sleep problems negatively affect health and suggest solutions for how many of the problems can be reversed.

项目摘要 患有慢性睡眠障碍的个体处于发展肠道功能障碍的高风险中，这可以 促进急性心血管和心脏代谢疾病。我的实验室最近发现，睡眠和肠道 双向关系。他们发现，在慢性睡眠不足的过程中，肠道受到了特别严重的损伤： 抑制导致该器官中活性氧（ROS）的积累，这反过来又导致氧化应激 动物的过早死亡。该实验室还发现了一种调节睡眠的肠道到大脑的肽能信号通路 深入关键是要确定睡眠量少和睡眠质量差对肠道生理产生的负面影响， 功能我将使用果蝇作为模型系统来研究基本的分子、细胞和功能关系 在睡眠和肠道之间。我的研究将验证睡眠不足导致肠道细胞组成改变的假设 在从睡眠不足中恢复的过程中促进增加睡眠深度。该提案的第一个目标将侧重于确定 长期睡眠不足的果蝇肠道细胞组成的变化。我认为睡眠不足会促进肠道干细胞 增殖并使子细胞偏向肠内分泌细胞命运（肠感觉细胞和分泌细胞）。我会把联合收割机 免疫荧光和荧光报告基因，以确定肠干细胞增殖和肠内分泌的变化 细胞命运决定。第二个目标是检查从慢性睡眠不足中恢复的苍蝇的睡眠质量和寿命。 我认为，长期睡眠不足导致的肠道细胞组成的变化促进了苍蝇的深度睡眠 从睡眠不足中恢复过来，以弥补睡眠不足。我将量化睡眠的深度， 睡眠不足的苍蝇在其一生中进行功能实验，以评估苍蝇是否分泌肽 肠内分泌细胞负责增加恢复期间的睡眠深度。我还将从功能上确定 这些肠内分泌细胞分泌的肽对从慢性睡眠丧失中恢复的果蝇的寿命的贡献。 确定肠道中的细胞变化如何影响该器官的功能及其在调节睡眠中的作用将是 这是理解双向睡眠-肠道关系的基础。更广泛地说，这项工作将有助于 了解睡眠问题如何对健康产生负面影响，并提出解决方案， 颠倒的。