Mechanical Clocks During Fetal Development

胎儿发育期间的机械钟

• 批准号: 10705665
• 负责人: Celeste M Nelson
• 金额: $ 113.4万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705665
• 关键词: Adult; Animals; Asthma; Biochemical; Biology; Birth; Cells; Chronic Disease; Complement; Congenital Abnormality; Coupled; Coupling; Defect; Development; Diffusion; Disease; Distant; Embryo; Embryonic Development; Ensure; Environment; Epithelium; Event; Fetal Development; Fetus; Frequencies; Genetic Transcription; Human; Image; Kidney Failure; Knockout Mice; Life; Liquid substance; Lung; Mechanics; Microfluidics; Modeling; Molecular; Morphogenesis; Muscle Contraction; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Organ; Patients; Periodicals; Process; Proliferating; Proteomics; Pulmonary Emphysema; Reporter; Sampling; Segmentation Clock Pathway; Signal Pathway; Signal Transduction; Smooth Muscle; Stereotyping; Stimulus; Testing; Time; Tissues; Transgenic Organisms; Work; circadian pacemaker; design; extracellular; fetal; innovation; lung development; mechanical force; mouse model; nephrogenesis; novel strategies; organ growth; organ on a chip; pancreas development; physical process; premature; pressure; stem cells; transcriptomics; transmission process; zygote

PROJECT SUMMARY Development is all about timing. From fertilized egg to newborn infant, embryonic development proceeds as a highly coordinated sequence of stereotyped events. The order and timing of each stage of the process, including the timing of tissue morphogenesis and differentiation of progenitor cells, are essential for building mature organs in time for birth. Defects in timing are associated with both congenital birth defects as well as chronic diseases in the adult, including asthma, emphysema, renal failure, and type II diabetes. What controls the tempo of development – the central metronome of the embryo – is one of the great mysteries of biology. Only a handful of molecular timers have been discovered to-date, including the circadian and segmentation clocks, both of which operate as transcriptional oscillators that are entrained by periodic activation of extracellular biochemical stimuli. However, it is unclear how biochemical signals that are transmitted by diffusion can couple the rates of development of organs that are separated by large distances within the embryo. We recently discovered unexpectedly that the rate of morphogenesis of the embryonic mammalian lung is entrained by mechanical forces from luminal fluid pressure, which controls the frequency of synchronized epithelial branching and smooth muscle contraction across the organ. These findings suggest the presence of a “mechanical clock” in the fetus. Because fluid pressure is transmitted instantaneously between distant tissues, a mechanical clock could synchronize the rates of development across organs, permitting coordinated maturation before birth. Here, we propose to investigate the coupling of lung, kidney, and pancreatic development, organs that are all connected by fluid within and around the embryo and that form via branching morphogenesis. We will define how the magnitude of pressure controls the rates of proliferation, differentiation, and morphogenesis using microfluidics approaches. We will also identify the oscillatory signaling pathways that are induced by pressure and investigate how fluid forces are transmitted between distant organs to ensure that their rates of development are coupled. We will combine organ-on-a-chip models, tissue-specific reporter animals, transgenic knockout mice, single-cell transcriptomics and proteomics, and quantitative time-lapse imaging analysis, and complement these with studies of human patient samples and mouse models of entrainment defects. This work will uncover how the shared mechanical environment of fetal organs permits them to grow and mature coordinately in time for birth, which is essential for designing new approaches to treat disorders associated with congenital defects and developmental prematurity, as well as chronic diseases in the adult.

项目摘要 从受精卵到新生婴儿，胚胎发育程序作为A 刻板的事件的高度协调序列。 包含组织形态发生和祖细胞的分化，对于建造是必不可少的 及时出生时的成熟器官。 成年人的慢性疾病，包括哮喘，肺气肿，肾衰竭和II型糖尿病。 发展的节奏 - 胚胎的中央节拍器 - 是生物学的最大奥秘之一。 迄今仅发现了少数分子计时器，包括昼夜节律和分割 时钟，两者都是作为转录振荡器操作的，这些振荡器被定期激活所夹住 但是，细胞外生化刺激尚不清楚Transmitt的生化信号如何 扩散可以融合由您内部大距离分离的器官的发展速率 胚胎。 肺部受到管腔流体压力的机械力，该力控制频率关闭 这些发现的同步上皮分支和平滑肌收缩 胎儿中的“机械时钟”。 在远处的组织之间，机械时钟可以同步器官之间的发育速率， 在这里允许在出生前协调成熟。 和胰腺发育，由液体连接的器官与胚胎相连，该形式 通过分支形态发生。 分化和使用微流体方法的形态发生。 信号通路由压力引起的诱导并研究流体力如何传播。 远处的器官确保他们的发展速度是双方的。 组织特异性的记者动物，转基因基因敲除小鼠，单细胞转录组学和蛋白质组学 定量的延时成像分析，并通过对人类患者样本的研究和 夹带缺陷的鼠标模型。 器官允许他们及时及时地协调出生，这对于设计新的至关重要 与先天性缺陷和发育前提相关的信任障碍的方法，以及 成人的慢性疾病。