Roles of mechanotransduction in organ regeneration and fibrosis

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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.