| NSF Org: |
CMMI Division of Civil, Mechanical, and Manufacturing Innovation |
| Recipient: |
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| Initial Amendment Date: | June 3, 2019 |
| Latest Amendment Date: | June 3, 2019 |
| Award Number: | 1905390 |
| Award Instrument: | Standard Grant |
| Program Manager: |
Lucy Zhang
CMMI Division of Civil, Mechanical, and Manufacturing Innovation ENG Directorate for Engineering |
| Start Date: | May 15, 2019 |
| End Date: | April 30, 2023 (Estimated) |
| Total Intended Award Amount: | $223,965.00 |
| Total Awarded Amount to Date: | $223,965.00 |
| Funds Obligated to Date: |
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| History of Investigator: |
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| Recipient Sponsored Research Office: |
5250 CAMPANILE DR SAN DIEGO CA US 92182-1901 (619)594-5731 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
5500 Campanile Drive San Diego CA US 92182-1931 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): | BMMB-Biomech & Mechanobiology |
| Primary Program Source: |
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| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.041 |
ABSTRACT
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.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
Fundamental processes in biology rely on cells sensing their environment and responding appropriately; in aging and disease, the capacity of cells to sense and respond is impaired. Emerging findings show that stress hormones, which are released into circulation in response to a physical or psychological threat, can impact cellular behavior by altering cellular mechanical behaviors, such as how much force cells generate on their surrounding environment. Mapping the circuitry of how stress hormones impact cell mechanical behaviors would enable new levels to predict and control cell behaviors for human health and disease applications.
This NSF BMMB Collaborative Research Award supported our project to define the molecular and physical mechanisms of how cells translate soluble stress hormone signals into changes in cellular mechanical behaviors. Specifically, we tested the hypothesis that stress hormone signaling through β-adrenergic receptors (βAR) regulates epithelial cell mechanotype, which is critical in physiological processes from tissue morphogenesis to wound healing to cancer progression. Using both experimental and computational methods, we discovered mechanisms of cellular force generation in mammary epithelial cells including both breast tumor cells and non-tumorigenic cells. We found that activation of b-adrenergic receptors in breast tumor cells operates through the molecules RhoA and ROCK to activate non-muscle myosin II (NMII) and increase cellular force generation. By contrast, non-tumorigenic cells do not show any significant change in force generation in response to βAR activation. We also determined that bAR activation increases tumor cell force generation by increasing the number of myosin II motors bound to actin, which is a protein that is integral for cellular structure and mechanical stability. We further determined that this mechanism contributes to βAR regulation of cell motility. Taken together, these findings establish a mechanism for how βAR alters tumor cell mechanical behaviors through βAR-RhoA-ROCK-NMII to increase cellular force generation and cell motility.
Mapping how epithelial cells process information from βAR agonists provides insight into fundamental physiological contexts where both stress hormones have been established to be regulators, for example in tissue morphogenesis, wound healing, and cancer. In the context of cancer, cellular force generation can reduce the porosity of a tumor and thereby contribute to impeded transport of chemotherapy drugs into the tumor to kill cancer cells. Finding new pathways to block cell contractility thus has potential to improve the efficacy of chemotherapy treatments. A deeper knowledge of the signaling pathways that regulate cancer cell mechanical behaviors could ultimately have therapeutic potential to advance human health. More broadly, these findings deepen our understanding of the scope of environmental cues that regulate cellular mechanical behaviors, which can have implications for human health or disease contexts including but not limited to fibrosis, wound healing, tissue regeneration, and tissue engineering.
Last Modified: 08/22/2023
Modified by: Parag Katira
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