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成生化信号，这一过程被称为 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。 我一直在开发一项研究计划，以阐明 机械转导在组织生长控制和疾病发展中的作用，目前的重点是 在器官损伤和修复过程中，机械转导如何控制再生和纤维化。这个 在这种疾病背景下理解机械转导的主要挑战是缺乏 关于机械转录体和由组合触发的信号级联的知识 力、细胞和微环境特有的因素。在这项提案中，我的目标是回答3个主要问题 促进我们在该领域的理解的问题：(I)机械转导起什么作用 在调节细胞功能和转录本方面，特别是在组织修复的背景下？(Ii) 连接质膜机械传感器的信号级联是什么？ 机械转录本？(Iii)生物力学提示和伤口愈合信号如何整合到 控制细胞功能和转录本？ 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 它们分别是研究机械转导和组织修复的经典模型。我们 将表征内皮细胞机械转导在肝再生和纤维化中的作用 主要使用(I)人原代内皮细胞体外或体外生物工程模型， 和(Ii)活体小鼠肝损伤模型。我的研究计划也将包括类似的研究 成纤维细胞机械转导与肺再生和纤维化的关系。 我预计我的研究计划将促进对 在正常和疾病情况下的机械转导，为识别新的 器官纤维化和其他疾病的机械信号级联反应的可用药靶点 异常的组织力学。

Project Summary 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 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 and repair. The main challenge in understanding mechanotransduction in this disease context 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? (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 mechanotransduction for 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. My research program will also include similar studies of fibroblast mechanotransduction and lung regeneration and fibrosis. I anticipate that my research program will advance the fundamental understanding of mechanotransduction in normal and diseased contexts, providing opportunities for identifying new druggable targets from mechano-signaling cascades for organ fibrosis and other diseases with aberrant tissue mechanics.