| NSF Org: |
CMMI Division of Civil, Mechanical, and Manufacturing Innovation |
| Recipient: |
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| Initial Amendment Date: | July 22, 2014 |
| Latest Amendment Date: | July 22, 2014 |
| Award Number: | 1362922 |
| Award Instrument: | Standard Grant |
| Program Manager: |
Michele Grimm
CMMI Division of Civil, Mechanical, and Manufacturing Innovation ENG Directorate for Engineering |
| Start Date: | August 1, 2014 |
| End Date: | January 31, 2019 (Estimated) |
| Total Intended Award Amount: | $387,061.00 |
| Total Awarded Amount to Date: | $387,061.00 |
| Funds Obligated to Date: |
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| History of Investigator: |
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| Recipient Sponsored Research Office: |
1 SILBER WAY BOSTON MA US 02215-1703 (617)353-4365 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
MA US 02215-1300 |
| 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
Mechanical stresses influence biological form and function. For normal functions, tissues must maintain stress at a preferred level a process known as tensional homeostasis. Various factors including injuries, diet, aging and genetic risk factors may disrupt tensional homeostasis, and loss of homeostasis promotes the progression of diseases including atherosclerosis, formation of aneurysm balloons, acute lung injury, and cancer. Although it is widely believed that tensional homeostasis traverses a wide range of length scales and that even single cells in isolation are capable of maintaining tensional homeostasis, preliminary data indicate that isolated cells are not capable of maintaining tensional homeostasis and that intercellular cooperation is required. This award will investigate how intercellular cooperation contributes to tensional homeostasis and to determine the underlying biophysical and biochemical mechanisms. The project will focus on homeostasis in vascular endothelial cells since vascular diseases are linked to a loss of tensional homeostasis. Results from this study will have a transformative impact on our understanding of the functional link between loss of tensional homeostasis and progression of diseases such as atherosclerosis and aneurysm. Furthermore, results of our study may provide insight into diseases such as cancer where the loss of tensional homeostasis is a hallmark of disease progression. The work will involve both undergraduate and graduate students and will be integrated into coursework.
The dominant paradigm in vascular biology is that tensional homeostasis exists across multiple length (and time) scales through the feedback control of intracellular mechanics and signaling in response to the externally imposed stresses. However, preliminary data from this study revealed that isolated cells could not maintain tensional homeostasis, whereas confluent multicellular clusters could, suggesting that cell-cell interactions might be necessary for homeostasis. This leads to a working hypothesis that direct cell-cell interactions are required for maintaining tensional homeostasis in the endothelium. This is accomplished either via mechanical interdependence between adjacent cells, or via molecular crosstalk between adherens junctions and focal adhesions. To test this hypothesis, traction forces in cellular clusters and in individual cells will be measured using a micropattern traction microscopy system that was developed by the PIs. This technique utilizes multiple, distinct adhesion ligands and is compatible with substrate strain application mimicking the stretch conditions in vivo, application of shear flow mimicking vascular wall shear stress, tunable substrate rigidity, and high resolution microscopy to measure cellular traction forces with less than 1 nN accuracy.
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.
Homeostasis is a fundamental concept in physiology which describes the ability of living systems to maintain stability of their physiological functions (e.g., body temperature, blood sugar level, blood pressure, calcium level, water balance, etc.) in responses to perturbations from their environment. Any breakdown in homeostasis is a hallmark of disease progression including atherosclerosis, hypertension, aneurysms, and cancer. Given the pluripotent role of mechanical stresses and strains in mechanobiology of cells, homeostasis is closely associated with the ability of cells to maintain their internal cytoskeletal stress (or tension) stable in response to external and internal perturbations. This is known as tensional homeostasis. While the concept of tensional homeostasis has been known for more than two decades, there have been very few quantitative studies of this phenomenon. Moreover, the mechanisms that are responsible for maintaining tensional homeostasis have been largely unknown. In this grant project, we carried out quantitative measurements on living cells and rigorous engineering analysis of the experimental data combined with mathematical modeling to gain insight into mechanisms that govern tensional homeostasis in living cells.
First, the basic science contributions of this grant resulted in six peer-reviewed publications. All these articles are original contributions. The work was presented at twelve national/international conferences and two invited talks.
Cells of different types (endothelial cells, fibroblasts, smooth muscle cells and cancer cells) were used in this study. We measured traction forces that cells apply to the substrate using our system for traction measurements that we developed previously. From these measurements, we were able to quantitatively assess stability of cytoskeletal tension over prolonged time intervals. We discovered that tensional homeostasis is cell type-dependent. In certain cell types (e.g., endothelial cells) tensional homeostasis can be achieved only in multicellular clusters, whereas in other cell types (e.g., fibroblasts) clustering is not required for homeostasis. By combining engineering analysis and mathematical modeling, we were able to identify several factors that influence tensional homeostasis. Those included the number of cell-substrate adhesions, stability of those adhesions, functional cell-cell adhesions, temporal variability of traction forces, their heterogeneity and their correlation, as well as the stiffness of the substrate. The impact of these factors on tensional homeostasis depended on the cell type. These were novel and key findings of this grant. Lastly, this grant project provided numerous training opportunities for young scientists-in-training. Thre PhD candidates, two MS candidates, and six undergraduate students worked on various aspects of this project.
Last Modified: 04/01/2019
Modified by: Dimitrije Stamenovic
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