CAREER: Leveraging Microphysiological Systems to Study Molecular Mechanisms of Pathological Angiogenesis

Recent advances in tissue engineering have led to the emergence of microphysiological systems (MPS) -- bioengineered microtissues that capture the complexities of intact tissue while leveraging the strengths of simpler cell culture systems. MPS are a powerful advanced new technology for basic and translational science. However, barriers to widespread MPS acceptance and adoption are still present. These include a need for more rigorous application of MPS to explore basic tissue biology, and a need for more comprehensive education on MPS technology. The overall goal of this project is to remove these barriers and promote greater use of MPS for basic research and STEM education. This will be accomplished through research aims using MPS to study how blood vessel growth becomes abnormal in diseases such as cancer. In parallel, this project will also develop new educational programming on MPS technology, which will increase public awareness about MPS, promote MPS adoption in basic research, and excite students to remain in the STEM education pipeline. Overall, this project significantly advances biomanufacturing and biomaterials by i) enhancing the basic science, engineering, and applicability of MPS and their underlying biological components; ii) integrating MPS into translation of basic biological principles towards identification of unique biomarkers; and iii) preparing the STEM education and workforce for a future that includes integrated use of MPS technology. For its research aims, this project will use vessel- and tumor-on-a-chip MPS models to study how healthy and diseased blood vessel growth (i.e., angiogenesis) is regulated by partial endothelial-to-mesenchymal transition (pEndoMT), a complex systems-level tissue process. First, dense spatiotemporal responses to growth factor and fluid flow will be used to generate an ODE model of pEndoMT and angiogenesis, with subsequent model validation and parameter refinement in healthy and diseased MPS systems. Following model construction, the presence of bistable pEndoMT state(s) will be compared under healthy and diseased signaling and microenvironmental contexts using vessel- and tumor-on-a-chip MPS. Second, multiomic sequencing of vessel- and tumor-on-a-chip MPS platforms will identify novel pEndoMT markers (and their epigenetic status) conserved across healthy and diseased angiogenesis, with validation in intact mouse tissue. Together, these research aims will demonstrate how MPS can provide powerful insights into the biological processes that govern physiological and pathological angiogenesis. 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. NSF Award ID: 2543698 | Program: 01003031DB NSF RESEARCH & RELATED ACTIVIT,01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Jennifer Fang | Institution: Tulane University, NEW ORLEANS, LA | Award Amount: $814,266 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2543698 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2543698.html