CAREER: Decoding the Mechanical Control of Tissue Growth

为了构建健康的组织和器官，细胞需要从环境中获得持续的生化和机械反馈。包括肿瘤生长在内的几种疾病与异常的组织硬化或软化有关，这是一种已知的导致或加剧疾病进展的机械效应。然而，这些机械效应是如何控制组织生长和疾病出现的，这在很大程度上仍然是未知的，因为没有方法可以揭示细胞是如何对这些机械信号做出反应的。这项由学院早期职业发展（Career）奖支持的研究将通过使用一系列尖端技术首次揭示细胞的机械环境以及它们在组织构建过程中对这种环境的直接反应，来克服这些困难。除了发现组织和器官生长的新基本机制之外，这项研究的结果将有助于许多组织工程应用，以及对癌症和其他与组织机械异常相关的疾病的理解和诊断，从而为社会做出贡献。此外，该项目将为代表性不足的学生提供许多参与跨学科研究项目的机会，从而促进工程教育。机械因素，如细胞微环境的力或机械特性，已知会影响培养条件下细胞的行为，但尚不清楚这些因素如何影响活体3D组织中的细胞。在三维多细胞系统中，特别是在组织和器官形成过程中，解决生物力学和机械生物学问题的关键必要步骤是能够定量测量这些系统中的内源性机械线索。利用两种新的基于微滴的技术，可以直接量化发育中的3D组织中机械力和机械特性的时空变化，该研究将揭示细胞在脊椎动物体轴伸长过程中感知到的不同机械信号，解码这些机械信号的时空特征，并量化细胞对受控机械刺激的机械反应。都在发育中的斑马鱼胚胎中。

In order to build healthy tissues and organs, cells need constant biochemical and mechanical feedback from their environment. Several diseases, including tumor growth, are linked to abnormal tissue hardening or softening, a mechanical effect known to either cause or exacerbate the progression of the disease. However, it remains largely unknown how these mechanical effects control tissue growth and the appearance of disease, simply because no methodologies existed to reveal how cells respond to these mechanical cues. The research supported by this Faculty Early Career Development (CAREER) award will overcome these difficulties by using a set of cutting-edge techniques to reveal for the first time the mechanical environment of cells and their response to this environment directly as tissues are being built. Beyond the discovery of new fundamental mechanisms underlying tissue and organ growth, the results of this research will contribute to society by helping in many tissue engineering applications as well as in the understanding and diagnosis of cancer and several other diseases associated with tissue mechanical abnormalities. Moreover, this project will provide many opportunities for underrepresented students to engage in interdisciplinary research projects, thereby promoting engineering education.Mechanical cues, such as forces or the mechanical properties of the cellular microenvironment, are known to affect the behavior of cells in culture conditions, but it is unknown how these affect cells in living 3D tissues. A key necessary step to approach biomechanics and mechanobiology questions in 3D multicellular systems, especially during the formation of tissues and organs, is being able to quantitatively measure the endogenous mechanical cues in these systems. Using two novel microdroplet-based techniques that enable a direct quantification of spatiotemporal variations in mechanical forces and mechanical properties within developing 3D tissues, the proposed research will reveal the differential mechanical cues that cells perceive during vertebrate body axis elongation, decode the spatial and temporal characteristics of such mechanical cues, and quantify the mechanical response of cells to controlled mechanical stimuli, all within the developing zebrafish embryo.