Roles of mechanotransduction in organ regeneration and fibrosis

项目摘要 环境生物力学信号在细胞生长和功能动态平衡中起着关键作用。 人类的许多疾病，如器官纤维化、心血管疾病和癌症， 与促进疾病进展的异常生物力学线索有关。然而，如何 细胞感知生物力学信号并将其传播为生化信号，这是一个已知的过程 作为机械转导，人们对此知之甚少。特别是，精确的信号转导 机械转导的机制和转录产物仍不清楚。揭开了 机械转导的作用和信号级联对于理解基本原理很重要 发展和疾病机制以及推进治疗策略。 我一直在开发一个研究程序，由R35GM142504支持，以阐明这些角色 和机械转导在组织生长控制和疾病发展中的机制， 机械转导如何控制器官再生和纤维化的研究进展 损伤、修复和致癌。在理解机械转导方面的主要挑战 这些疾病的背景是缺乏机械转录体和信号转导的知识 由特定于力、特定于细胞和特定于微环境的组合触发的级联 各种因素。在这项建议中，我打算回答三个主要问题，以增进我们对 领域：(I)机械转导在调节细胞功能中起什么作用 和转录本，特别是在组织修复和纤维化的背景下？(Ii)什么是 连接质膜机械感受器和机械转录体的信号级联？ (Iii)生物力学线索和伤口愈合信号如何整合以控制细胞功能 还有抄本呢？ 我将使用内皮细胞和肝脏作为我的主要模型来研究这些问题，因为它们是 分别研究机械转导和组织修复的经典模型。我们会 血管内皮细胞机械转导在肝再生和肝纤维化中的作用 使用(I)体外或体外人原代内皮细胞生物工程模型，以及(Ii)在 活体小鼠肝损伤模型。 我们建议在最初的体外和体外实验中使用阿凡达Duo系统 求婚。这个系统可以使我们从内部制造几个设备的努力中解脱出来 执行原始建议中的工作，使我们能够更高效地进行实验 在R35GM142504中提出的生物力学和生物物理环境下 类似于生理和病理生理条件。 我希望这台新仪器能让我的研究项目更有效地推进 对正常和疾病环境中的机械转导的基本理解，因此 帮助从器官纤维化的机械信号级联反应中识别新的可用药靶点 其他疾病。

Project Abstract Environmental biomechanical cues play a critical role in cell growth and functional homeostasis. Many human diseases, such as organ fibrosis, cardiovascular diseases, and cancers, have been associated with aberrant biomechanical cues that promote disease progression. However, how cells sense and propagate biomechanical cues into biochemical signals, a process known as mechanotransduction, is poorly understood. In particular, the precise signaling transduction mechanisms and transcriptional outputs of mechanotransduction remain unknown. Unveiling the roles and signaling cascades of mechanotransduction is important for understanding fundamental development and disease mechanisms and for advancing therapeutic strategies. I have been developing a research program, supported by R35GM142504, to elucidate the roles and mechanisms of mechanotransduction in tissue growth control and disease development, with a current focus on how mechanotransduction controls regeneration and fibrosis during organ injury, repair, and carcinogenesis. The main challenge in understanding mechanotransduction in these disease contexts is the lack of knowledge of mechanotranscriptomes and signaling cascades that are triggered by a combination of force-, cell-, and microenvironment-specific factors. In this proposal, I aim to answer 3 main questions to advance our understanding in the field: (i) what role does mechanotransduction play in regulating cellular functions and transcriptomes, particularly in the context of tissue repair and fibrosis? (ii) what are the signaling cascades that connect plasma membrane mechanosensors to mechanotranscriptomes? (iii) how do biomechanical cues and wound-healing signals integrate to control cellular functions and transcriptomes? I will use endothelial cells and the liver as my main models to study these questions, as they are classical models for studying mechanotransduction and tissue repair, respectively. We will characterize endothelial mechanotransductionfor its roles in liver regeneration and fibrosis mainly using (i) in vitro or ex vivo bioengineered models with human primary endothelial cells, and (ii) in vivo mouse models of liver injury. We propose to use an Avatar Duo System for the in vitro and ex vivo experiments in the original proposal. This system can save us from the efforts of in-house manufacturing several devices to perform the work in the original proposal, more efficiently enabling us to conduct the experiments proposed in R35GM142504 under the biomechanical and biophysical environments that resemble physiological and pathophysiological conditions. I expect that this new instrument will allow my research program to more efficiently advance the fundamental understanding of mechanotransduction in normal and diseased contexts, thus helping identify new druggable targets from mechano-signaling cascades for organ fibrosis and other diseases.