Collaborative Research: Understanding How Stress Hormone Signaling Impacts Cellular Mechanotype

合作研究：了解应激激素信号传导如何影响细胞机械类型

• 批准号: 1905390
• 负责人: Parag Katira
• 金额: $ 22.4万
• 依托单位: San Diego State University Foundation
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1905390&HistoricalAwards=false
• 关键词: Collaborative; Research; Understanding; How; Stress

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.

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。新的研究结果表明，应激激素等化合物会因身体或心理威胁而释放到血液中，通过改变细胞的机械特性和反应来影响细胞的行为。 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。这些问题的答案将加深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。 了解这些过程对于推进与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有助于深入了解包括少数民族社区在内的不同群体存在的健康差异。 该项目还将通过一年一度的机械生物学研讨会促进科学的多样性，以支持来自代表性不足群体的学生的研究培训。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？该研究将检验压力激素信号通过β-肾上腺素受体（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类型，该项目的结果将推进与细胞稳态相关的知识。 此外，它将支持识别干预与心理压力、衰老和疾病相关的细胞稳态丧失的杠杆点。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。这些观察结果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。通过将实验观察与计算模型相结合，该项目的最终目标是预测应激激素如何诱导细胞机械类型的变化，以及对从伤口愈合到癌症的生理和疾病背景下的细胞迁移和侵袭的后续影响。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Chemo-Mechanical Factors That Limit Cellular Force Generation

• DOI: 10.3389/fphy.2022.831776
• 发表时间: 2022-02
• 作者: Esteban Vazquez-Hidalgo;C. Farris;A. Rowat;Parag Katira

To lead or to herd: optimal strategies for 3D collective migration of cell clusters

• DOI: 10.1007/s10237-020-01290-y
• 发表时间: 2020-01-29
• 期刊: BIOMECHANICS AND MODELING IN MECHANOBIOLOGY
• 影响因子: 3.5
• 作者: Collins, Tyler A.;Yeoman, Benjamin M.;Katira, Parag
• 通讯作者: Katira, Parag