Roles of mechanotransduction in organ regeneration and fibrosis

力转导在器官再生和纤维化中的作用

• 批准号: 10439911
• 负责人: ZHIPENG MENG
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439911
• 关键词: Biochemical; Biomechanics; Biomedical Engineering; Cardiovascular Diseases; Cell membrane; Cell physiology; Cells; Choristoma; Cues; Development; Disease; Disease Progression; Endothelial Cells; Endothelium; Fibroblasts; Fibrosis; Genetic Transcription; Growth; Homeostasis; Human; In Vitro; Knowledge; Liver; Liver Fibrosis; Liver Regeneration; Malignant Neoplasms; Mechanics; Modeling; Molecular; Natural regeneration; Organ; Output; Pathway interactions; Play; Process; Pulmonary Fibrosis; Research; Role; Signal Transduction; Study models; Therapeutic; cell growth; human disease; in vivo; injury and repair; liver injury; lung regeneration; mechanotransduction; mouse model; new therapeutic target; organ injury; organ regeneration; programs; tissue regeneration; tissue repair; transcriptome; wound healing

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.

项目摘要 环境生物力学线索在细胞生长和功能稳态中起着关键作用。 许多人类疾病，如器官纤维化、心血管疾病和癌症，已经被发现。 与促进疾病进展的异常生物力学线索相关。但如何 细胞感知并将生物力学线索传播为生化信号，这一过程被称为 机械传导，知之甚少。特别是，精确的信号传导 机械转导的机制和转录输出仍然未知。揭开 机械传导的作用和信号级联对于理解基本的 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计划，以阐明的作用和机制， 机械转导在组织生长控制和疾病发展，目前的重点是 机械传导如何控制器官损伤和修复过程中的再生和纤维化。的 理解这种疾病背景下的机械转导的主要挑战是缺乏 机械转录组和信号级联的知识，由组合触发 力、细胞和微环境的特定因素。在这篇文章中，我想回答三个主要问题。 问题，以促进我们在该领域的理解：（i）机械转导发挥什么作用 在调节细胞功能和转录组，特别是在组织修复的背景下？（二） 连接质膜机械传感器的信号级联是什么 机械转录组(iii)生物力学提示和伤口愈合信号如何整合， 控制细胞功能和转录组 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， 它们分别是研究机械传导和组织修复的经典模型。我们 将描述内皮机械转导在肝再生和纤维化中的作用 主要使用（i）人原代内皮细胞的体外或离体生物工程模型， 和（ii）肝损伤的体内小鼠模型。我的研究计划也将包括类似的研究 成纤维细胞机械传导和肺再生和纤维化的过程。 我希望我的研究项目能促进对 在正常和患病的情况下，机械转导，提供了机会，以确定新的 从机械信号级联的药物靶向器官纤维化和其他疾病， 异常的组织结构