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.

Project Start
Project End
Budget Start
2019-05-15
Budget End
2022-04-30
Support Year
Fiscal Year
2019
Total Cost
$476,764
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095