Cellular Integration of Physical Cues in the Microenvironment

在体内，我们的细胞不断受到来自许多来源的机械力的影响。这包括肺的扩张、心脏的跳动、血液的流动以及运动时肌肉的收缩。此外，我们器官和组织的机械特性（如硬度）对我们身体的功能和发育有着深远的影响。细胞环境的机械刚度影响体内许多不同的过程，如干细胞的命运、细胞的生长和死亡、新肌肉组织的形成，甚至癌症的扩散或心脏病的进展。重要的是，在体内，细胞可以同时暴露于刚度的快速变化以及压缩和拉伸的影响。虽然人们已经认识到细胞对局部环境中的机械信号很敏感，但细胞用来感知和响应物理信息的确切机制仍然知之甚少。然而，由于这些感知能力对我们的发展、成长和健康至关重要，因此了解它们是如何运作的势在必行。在这个研究项目中，我们将深入研究控制细胞感知和响应环境中机械信号的能力的物理和分子机制。利用最先进的生物物理和遗传方法，我们将对细胞对物理力的最早反应进行实时的机械理解。我们还开发了一些技术，使我们能够研究细胞对同时暴露于变形和环境刚度变化的反应。采用高度跨学科的生命和物理科学训练和方法，我们将能够解决细胞生物学中的这些基本问题。利用细胞对物理力和机械特性的敏感性已经被提出作为控制干细胞命运或为移植治疗细胞做准备的手段。另外，测量细胞物理特性的变化被认为是检测体内和血液中癌细胞的可行方法。因此，增强我们对细胞生物学机械方面的基本知识有可能指导未来医学检测和疾病治疗的发展。重要的是，渥太华大学的佩林实验室已经贡献了一些基本的新知识，这些知识已经在这些领域中找到了潜在的应用。佩林实验室产生的新知识可能通过开发下一代医疗保健检测和治疗技术影响加拿大人。该研究计划将培养下一代加拿大高素质人才（HQP），以开发具有许多潜在应用的令人兴奋和革命性的新知识。HQP将接受高级细胞/分子生物学、高级显微镜、定量分析、计算机编程、3D打印、微加工、设备设计、构造和原型制作方面的培训。HQP将在一个跨学科的实验室中工作和协作，为以后在学术界或工业界的职业生涯获得高度可转移的技能。精通生物学和物理学语言的HQP是本研究计划的核心目标，也是本工作的任何最终下游应用。在佩林实验室接受培训的HQP已经走上了不同的职业生涯，直接影响了加拿大在能源，汽车，医疗保健和生物科学行业的知识型经济。

In the body, our cells are constantly subjected to mechanical forces arising from many sources. This can include the expansion of our lungs, the beating of our heart, our blood flow and the contraction of our muscles as we move. Furthermore, the mechanical properties of our organs and tissues (such as stiffness) can have a profound effect on the functioning and development of our bodies. The mechanical stiffness of the cellular environment influences many diverse processes in the body, such as stem cell fate, cell growth and death, the formation of new muscle tissue and even the spread of cancer or the progression of heart disease. Importantly, in the body, cells can be simultaneously exposed to rapid changes in stiffness as well as the effects of compression and stretch. Although it has become well appreciated that cells are sensitive to mechanical cues in their local environment, the exact mechanisms cells use to sense and respond to physical information remain poorly understood. However, because these sensing abilities are so crucial our development, growth and well being, it is imperative to understand how they operate. In this research program, we will delve into the physical and molecular mechanisms that govern the ability of a cell to sense and respond to mechanical cues in its environment. Utilizing state of the art biophysical and genetic approaches we will develop a mechanistic understanding of the earliest response of a cell to physical forces in real time. We have also developed techniques that will allow us to examine how cells respond to the simultaneous exposure to deformation and changes in the stiffness of their environment. Employing highly interdisciplinary life and physical science training and methodologies, we will be able to address these fundamental questions in cell biology. Exploiting the sensitivity of cells to physical forces and mechanical properties has already been proposed as means to control stem cell fate or precondition therapeutic cells for transplantation. Alternatively, measuring changes in the physical properties of cells is thought to be a viable means of detecting cancerous cells in the body and bloodstream. Therefore, enhancing our fundamental knowledge about the mechanical aspects of cell biology has the potential to direct the development of future medical detection and treatments of disease. Importantly, the Pelling Lab, at the University of Ottawa, has already contributed fundamental new knowledge that has found potential applications in some of these areas. The new knowledge generated by the Pelling Lab may impact Canadians through the development of next generation healthcare detection and treatment technologies. This research program will train the next generation of Canadian highly qualified personnel (HQP) to develop exciting and revolutionary new knowledge with many potential applications. HQP will receive training in advanced cell/molecular biology, advanced microscopy, quantitative analysis, computer programming, 3D printing, microfabrication, device design, construction and prototyping. HQP will work and collaborate within an interdisciplinary laboratory, gaining highly transferable skills for later careers in academia or industry. HQP who are fluent in the languages of biology and physics are central to the objectives of this research program as well as any eventual downstream applications of this work. HQP who have been trained in the Pelling Lab have gone on to diverse careers that have directly impacted Canada’s knowledge based economy in the energy, automobile, healthcare and bioscience industries.