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，细胞对这种环境的感知和反应能力经常受到损害。新的发现表明，应激激素等化合物在受到身体或心理威胁时释放到血液中，可以通过改变细胞的机械性能和反应来影响细胞的行为。细胞的这些特征被称为其机械表型--或机械表型--包括细胞硬度和力的产生。这个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型反应。这些问题的答案将提高对细胞如何在环境变化时保持或适应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潜在特征。了解这些过程对于促进伤口愈合和癌症进展相关的应用和诊断机会非常重要。这些生理过程与压力、年龄和疾病的关系也将提供对包括少数族裔社区在内的各种群体存在的健康差距的洞察。该项目还将通过每年一次的机械生物学讲习班促进科学多样性，以支持对代表性不足群体的学生进行研究培训。这个项目是由两个研究问题推动的：(1)应激激素调节细胞机型的机制是什么；(2)应激激素如何显著影响细胞-基质相互作用？这项研究将验证应激激素信号通过β-肾上腺素能受体(Beta-AR)调节上皮细胞机械型的假设。通过定义上皮细胞如何整合来自应激激素的信号来调节其机械型，该项目的结果将促进与细胞动态平衡相关的知识。此外，它还将支持确定杠杆点，以干预与心理应激、衰老和疾病相关的细胞内稳态的丧失。这项研究得到了高通量机械分型平台的支持，用于测量细胞变形性的微柱法，以及细胞生物学中的常规工具(如Western blotting)，用于通过Beta-AR激活来量化蛋白质的激活水平。将使用先进的成像方法测量细胞细胞骨架和细胞-基质界面上的分子水平变化。这些观察将与细胞力产生的机械计算模型相结合，以剖析特定分子在驱动细胞对应激激素的机械型反应中的作用。通过将实验观察和计算模型相结合，该项目的最终目标是预测应激激素如何在从伤口愈合到癌症的生理和疾病环境中诱导细胞机械型的变化以及由此对细胞迁移和侵袭的影响。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.