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: 10798540
• 负责人: ZHIPENG MENG
• 金额: $ 9.92万
• 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/10798540
• 关键词: Award; Biochemical; Biological Process; Biomechanics; Biomedical Engineering; Biophysics; Cardiovascular Diseases; Cell membrane; Cell physiology; Cells; Choristoma; Complex; Cues; Development; Devices; Disease; Disease Progression; Endothelial Cells; Endothelium; Environment; Fibrosis; Funding; Genetic Transcription; Growth; Homeostasis; Human; In Vitro; Knowledge; Liver; Liver Fibrosis; Liver Regeneration; Malignant Neoplasms; Mechanics; Modeling; Molecular; Natural regeneration; Organ; Output; Pathway interactions; Physiological; Play; Process; Research; Role; Signal Transduction; Study models; System; Therapeutic; Work; carcinogenesis; cell growth; equipment acquisition; experimental study; human disease; in vivo; instrument; liver injury; manufacture; mechanotransduction; mouse model; new therapeutic target; organ injury; organ regeneration; programs; repaired; tissue regeneration; tissue repair; transcriptome; wound healing

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.

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信号转化为生化信号， 作为机械传导，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，由R35GM142504支持，以阐明作用 以及组织生长控制和疾病发展中的机械传导机制， 目前的重点是机械转导如何控制器官再生和纤维化， 损伤、修复和致癌作用。理解机械转导的主要挑战是 这些疾病的背景是缺乏机械转录组和信号传导的知识， 由特定于力、细胞和微环境的组合触发的级联 因素在这份提案中，我旨在回答三个主要问题，以促进我们对 领域：（i）机械传导在调节细胞功能中起什么作用 和转录组，特别是在组织修复和纤维化的背景下？(ii)有哪些 连接质膜机械感受器和机械转录组的信号级联？ (iii)生物力学信号和伤口愈合信号是如何整合来控制细胞功能的 和转录组吗 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， 经典模型研究mechanotransduction和组织修复。我们将 表征内皮机械转导，主要是因为其在肝再生和纤维化中的作用， 使用（i）具有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。 我们建议使用Avatar Duo系统进行原始的体外和离体实验， 提议该系统可以使我们从内部制造多个设备的努力中解脱出来， 执行原始提案中的工作，使我们能够更有效地进行实验 R35GM142504在生物力学和生物物理环境下提出， 类似于生理和病理生理条件。 我希望这种新仪器将使我的研究计划更有效地推进 对正常和疾病背景下机械传导的基本理解，因此 帮助从器官纤维化的机械信号级联中识别新的可药用靶点， 其它疾病