CAREER: Decoding the Mechanical Control of Tissue Growth

为了构建健康的组织和器官，细胞需要来自环境的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组织硬化或软化有关，这种机械效应已知会导致或加剧疾病的进展。然而，这些机械效应如何控制组织生长和疾病的出现在很大程度上仍然是未知的，只是因为没有方法论来揭示细胞如何对这些机械信号做出反应。这项由学院早期职业发展(Career)奖支持的研究将通过使用一套尖端技术首次揭示细胞的机械环境及其在组织构建过程中直接对这种环境的反应，从而克服这些困难。除了发现组织和器官生长的新的基本机制外，这项研究的结果将有助于许多组织工程应用，并有助于理解和诊断癌症和其他几种与组织机械异常相关的疾病。此外，该项目将为未被充分代表的学生提供许多参与跨学科研究项目的机会，从而促进工程学教育。众所周知，力或细胞微环境的机械特性等机械提示会影响细胞在培养条件下的行为，但这些因素如何影响活的3D组织中的细胞尚不清楚。在三维多细胞系统中，尤其是在组织和器官的形成过程中，解决生物力学和力学生物学问题的一个关键的必要步骤是能够定量地测量这些系统中的内源性机械线索。利用两种基于微滴的新技术，能够直接量化正在发育的3D组织中机械力和机械特性的时空变化，拟议的研究将揭示脊椎动物体轴伸长过程中细胞感知的不同机械线索，解码这种机械线索的空间和时间特征，并量化细胞对受控机械刺激的机械反应，所有这些都发生在斑马鱼胚胎中。

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.