Mechanisms of Physiological Organ Shrinkage

生理器官萎缩的机制

• 批准号: 10375998
• 负责人: Lucy Erin O'brien
• 金额: $ 47.89万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375998
• 关键词: Address; Adopted; Adult; Anatomy; Animals; Apoptosis; Apoptotic; Behavior; Biology; Calcium Oscillations; Celiac Disease; Cell Count; Cell Lineage; Cell Therapy; Cell division; Cells; Complex; Data; Daughter; Digestive Physiology; Disease; Drosophila genus; Endotoxemia; Enterocytes; Equation; Equilibrium; Experimental Models; Famines; Food; Future; Genetic; Giardiasis; Goals; Growth; Health; Human; Image; Individual; Ingestion; Intestines; Invertebrates; Investigation; Knowledge; Label; Laboratories; Laboratory Study; Mammals; Mammary gland; Mechanics; Methods; Midgut; Mitosis; Modeling; Modernization; Molecular; Monitor; Nutrient; Organ; Organ Size; Parenteral Nutrition; Pathologic; Pathway interactions; Periodicity; Physiological; Protocols documentation; Refractory; Regulation; Reporter; Research; Rodent; Siblings; Side; Signal Transduction; Skeletal Muscle; Skin; Small Intestines; Starvation; Testing; Time; Tissues; Transcription Coactivator; Translating; Undifferentiated; Wild Animals; Withdrawal; Work; base; body cavity; cell behavior; fly; frontier; genetic manipulation; human disease; in vivo; in vivo monitoring; innovation; mature animal; mechanical force; optogenetics; promoter; purge; response; serial imaging; stem cell differentiation; stem cell division; stem cells; tool; virtual

PROJECT SUMMARY Many adult organs--for instance, intestine, mammary gland, skeletal muscle, skin—respond to reduced levels of functional demand by shrinking their physical size. In these organs, cells are lost faster than they are made, leading to a reduction in total cell number. The intestine is a broadly conserved exemplar of demand- driven organ shrinkage. In wild animals, cyclic periods of starvation cause intestinal size to shrink by 60-75%. Humans also undergo healthy intestinal shrinkage, but excessive or dysregulated cell loss can quickly become pathological, as seen in enteropathies like celiac sprue, endotoxemia, and giardiasis. Yet—unlike the mechanisms that balance cell division/loss during everyday turnover—the mechanisms that tune cell imbalance for physiological shrinkage are virtually unknown. The roadblock to mechanistic investigation of intestinal shrinkage has been the lack of a tractable laboratory model, which must allow cells (and their dynamic behaviors) to be monitored across time and must possess cell-specific markers and other tools to facilitate mechanistic studies. Historically, studies used rodents, but modern research protocols cannot replicate natural famine/feast cycles. My lab has developed a new invertebrate model of intestinal shrinkage that is both tractable and genetically manipulable: the Drosophila adult midgut, akin to the vertebrate small intestine. We demonstrate that intestinal shrinkage is conserved in Drosophila, and we document that its underlying basis is the massive squeezing-out of now-superfluous enterocytes through active extrusion. Here, we investigate intestinal shrinkage from both sides of the equation for net cellular balance: mature cell loss (Aim 1) and stem cell capacity (Aim 2). Our studies leverage the midgut’s superlative toolkit of cell- specific genetic reporters and our own pioneering innovations for real-time and longitudinal imaging of functioning midguts inside live animals. In Aim 1, we ask how the gut senses loss of ingested food— mechanical compression, lack of nutrients, or both. We test if two known regulators of extrusion, the transcriptional co-activator YAP/Yorkie and intercellular Ca2+ waves, function during shrinking to increase extrusions. Third, we probe whether a shrinking gut regulates cell extrusions at the organ scale or at the level of individual cells. In Aim 2, we seek the mechanisms that cause a 75% culling of the stem cell pool during shrinkage—even as stem cell mitoses paradoxically increase. We will test if stem cells initiate non-self- renewing divisions, adopt terminal fates directly, and/or activate apoptosis. The fly gut’s digestive physiology, stem cell lineages, and molecular regulation are similar to humans. Hence by elucidating the cell-to-organ scale mechanisms that operate at this frontier of tissue biology, this project may yield leads for therapies to treat cellular imbalances in human disease.

项目摘要 许多成年器官 - 实例，肠道，乳腺，骨骼肌，皮肤 - 响应减少 功能需求水平通过缩小其身体大小。在这些器官中，细胞损失的速度比它们更快 制造，导致总细胞数量减少。肠道是需求的广泛保守的典范 - 驱动器官收缩。在野生动物中，饥饿的循环周期会导致肠道大小缩小60-75％。 人类还经历健康的肠道收缩 如腹腔泉，内毒素血症和贾第鞭毛疾病等肠道外植物中所见。然而 - 不像 平衡细胞分裂/每天营业额损失的机制 - 调整电池的机制 物理收缩的不平衡实际上是未知的。 肠收缩的机械投资的障碍是缺乏可行的 实验室模型，必须允许细胞（及其动态行为）跨时间监控，并且必须 拥有特异性标记和其他工具来促进机械研究。从历史上看，使用研究 啮齿动物，但现代研究方案无法复制自然农场/盛宴周期。 我的实验室已经开发了一种新的无脊椎动物肠收缩模型 遗传操作：果蝇成年中肠，类似于脊椎动物小肠。我们证明 肠道收缩在果蝇中是保守的，我们记录了它的基础是巨大的 通过主动延伸挤出现在呈现的肠细胞。 在这里，我们研究了从方程式两侧的肠收缩以进行净细胞平衡：成熟 细胞丢失（AIM 1）和干细胞容量（AIM 2）。我们的研究利用中肠的细胞最高级工具包 特定的遗传记者和我们自己的开创性创新，用于实时和纵向成像 活动物中的中肠运行。在AIM 1中，我们询问肠道感觉如何失去摄入的食物 - 机械压缩，缺乏营养或两者兼而有之。我们测试了两个已知的扩展调节剂， 转录共激活器yap/Yorkie和细胞间Ca2+波，在收缩期间的功能增加以增加 扩展。第三，我们探测收缩的肠道是否调节器官尺度或水平的细胞延伸 单个细胞。在AIM 2中，我们寻求引起75％干细胞池的机制 收缩 - 即使是干细胞有丝分裂的矛盾增加。我们将测试干细胞是否启动非自身 更新划分，直接采用末端命运和/或激活凋亡。 蝇肠的消化生理学，干细胞谱系和分子调节类似于人类。 因此，通过阐明在组织生物学领域运作的细胞到器官量表机制， 项目可能会产生用于治疗人类疾病细胞失衡的疗法的铅。