This Faculty Early Career Development (CAREER) program will investigate endothelial cell-cell junctions - the lining of blood vessels and lymphatics. This work will first study the relationship between the form, function, and mechanics of these junctions. This work will then study how these features may be regulated to influence the integrity of the endothelial barrier. Endothelial cells form a critical semi-permeable barrier that controls the flux of ions, molecules, and cells into and out of vasculature. When an organism is healthy, the integrity of the endothelial cell barrier is tightly regulated. It can become dysregulated in conditions such as cardiovascular disease, cancer, or neurological diseases. The dysregulation can be in the form of spatial heterogeneity or a change in temporal dynamics. Regardless, this dysregulation poses a challenge for drug delivery. Cells exposed to the same environment can demonstrate phenotypic (form) differences. These cell-cell heterogeneities may have important functional significance. This work is important because a better understanding of the links between endothelial cell-cell junction form, function, and mechanics could lead to image-based functional predictions about endothelial barrier integrity in both models and in living vessels. These predictions could ultimately lead to improved drug delivery methods. This research project will employ a multidisciplinary approach that integrates aspects of engineering, biology, and physics using novel software. The research project will also develop outreach initiatives featuring a series of research training modules for undergraduate and graduate students, partnerships with rural high schools, new labs and problem sets that synergize research and education in an undergraduate biomechanics class, a podcast highlighting diverse experiences in STEM careers, and training and mentoring efforts. As an award to an early-career researcher, completion of the research and outreach work will launch the investigator's career in both research and outreach.
The specific goal of the research is to discover how local alterations in endothelial cell-cell junction phenotype, and its dynamic rearrangements, contribute to local permeability of the endothelium to molecules and cells, and the degree to which this relationship is conserved across varying mechanical conditions, genetic alterations, junction types, and vascular beds from which the endothelial cells are derived. The research objectives are to (1) determine the role of endothelial cell-cell junction phenotype in controlling local permeability of the endothelium; (2) assess how endothelial cell-cell junction mechanics influence junction phenotype in response to external mechanical cues; and (3) determine how dynamic changes in endothelial cell-cell junction phenotype and mechanics contribute to local permeability of the endothelium. This work will establish the potential for a novel systems mechanobiology approach using microfabricated vascular models, molecular biology, advanced microscopy techniques, and custom software for quantitative analysis of the form, function, and mechanics of cell-cell junctions in the vascular endothelium. The following questions regarding endothelial cell mechanobiology will be answered: (i) can endothelial cell-cell junction phenotype and/or dynamics be used to quantitatively predict local permeability to molecules and/or cells; (ii) does intercellular junction phenotype quantitatively correlate with cell-cell or cell-matrix tension; and (iii) how do external mechanical cues alter intracellular signaling pathways to shift intercellular junction phenotypes and local barrier function? The project will allow the PI to advance knowledge in the field of mechanobiology, develop new model systems and quantitative analysis tools for broad use across bioengineering applications, and form the infrastructure for a transformative education, mentoring, and outreach program.
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.
