Collaborative Research: Understanding How Stress Hormone Signaling Impacts Cellular Mechanotype

生物体内发育和调节的基本过程依赖于细胞感知其环境并做出适当的反应。在衰老和疾病中，细胞感知和响应环境的能力常常受到损害。 Emerging findings show that compounds such as stress hormones, which are released into the blood in response to a physical or psychological threats, can impact the behavior of cells by altering their mechanical properties and responses. 细胞的这些特征被称为机械表型或机械型，包括细胞硬度和力的产生。该项目的目标是了解细胞如何将应激激素的存在转化为机械反应。这些问题的答案将增进对细胞如何随着环境变化而维持或调整其行为和特性的理解。 这是正常组织发育和生长以及疾病进展的一个关键的基本特征。 Understanding these processes is important to advancing applications and diagnostic opportunities related to wound healing and cancer progression. The relationship of these physiological processes to stress, age, and disease will also provide insight into health disparities that exist for various groups, including minority communities. The project will also promote diversity in science through an annual Mechanobiology Workshop to support the research training of students from underrepresented groups.该项目由两个研究问题驱动：（1）应激激素调节细胞机械型的机制是什么； (2) 应激激素如何通过信号影响细胞-基质相互作用？ The research will test the hypothesis that stress hormone signaling through Beta-adrenergic receptors (Beta-AR) regulates epithelial cell mechanotype. By defining how epithelial cells integrate signals from stress hormones to regulate their mechanotype, results from this project will advance knowledge related to cellular homeostasis. In addition, it will support the identification of points of leverage to intervene in the loss of cellular homeostasis that is associated with psychological stress, aging, and disease.该研究通过测量细胞变形性的高通量机械分型平台、量化细胞牵引应力的微柱分析以及量化 Beta-AR 激活的蛋白质激活水平的细胞生物学传统工具（例如蛋白质印迹）来实现。将使用先进的成像方法测量细胞骨架内和细胞-基质界面的分子水平变化。 These observations will be coupled with mechanistic computational models of cellular force generation to dissect the role of specific molecules in driving cellular mechanotypic response to stress hormones. By integrating experimental observations with computational modeling, the ultimate goal of this project is to predict how stress hormones induce changes in cellular mechanotype and the consequent effects on cell migration and invasion in physiological and disease contexts from wound healing to cancer.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Fundamental processes of development and regulation within organisms rely on cells sensing their environment and responding appropriately. In aging and disease, the capacity of cells to sense and respond to this environment is often impaired. Emerging findings show that compounds such as stress hormones, which are released into the blood in response to a physical or psychological threats, can impact the behavior of cells by altering their mechanical properties and responses. These characteristics of a cell are known as their mechanical phenotype - or mechanotype - and include cell stiffness and force generation. The goal of this project is to understand the way in which cells translate the presence of stress hormones into mechanotypic responses. The answers to these questions will improve understanding of how cells maintain or adapt their behavior and properties as their environments change. This is a key underlying feature of normal tissue development and growth as well as disease progression. Understanding these processes is important to advancing applications and diagnostic opportunities related to wound healing and cancer progression. The relationship of these physiological processes to stress, age, and disease will also provide insight into health disparities that exist for various groups, including minority communities. The project will also promote diversity in science through an annual Mechanobiology Workshop to support the research training of students from underrepresented groups. This project is driven by two research questions: (1) what is the mechanism of how stress hormones regulate cell mechanotype; and (2) how does stress hormone signally impact cell-matrix interactions? The research will test the hypothesis that stress hormone signaling through Beta-adrenergic receptors (Beta-AR) regulates epithelial cell mechanotype. By defining how epithelial cells integrate signals from stress hormones to regulate their mechanotype, results from this project will advance knowledge related to cellular homeostasis. In addition, it will support the identification of points of leverage to intervene in the loss of cellular homeostasis that is associated with psychological stress, aging, and disease. The research is enabled by a high throughput mechanotyping platform to measure cell deformability, micropillar assays to quantify cellular traction stresses, as well as conventional tools in cell biology (such as western blotting) to quantify levels of protein activation with Beta-AR activation. Molecular-level changes within the cell cytoskeleton and at the cell-matrix interface will be measured using advanced imaging methods. These observations will be coupled with mechanistic computational models of cellular force generation to dissect the role of specific molecules in driving cellular mechanotypic response to stress hormones. By integrating experimental observations with computational modeling, the ultimate goal of this project is to predict how stress hormones induce changes in cellular mechanotype and the consequent effects on cell migration and invasion in physiological and disease contexts from wound healing to cancer.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.