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Gooch receives two-year research grant from American Heart Association
Dr. Keith Gooch, professor, Biomedical Engineering was recently awarded a two-year grant from the American Heart Association for $154,000 to study the mechanical regulation of cardiac phenotype. Dr. Pamela Lucchesi, chair of Basic Sciences and professor of Physiology, Geisinger Commonwealth School of Medicine is the PI of a sub-award. This is the second award that the research team of Drs. Gooch and Lucchesi are recipients of in this general research area, which grew out of his sabbatical in her laboratory. Assistant Professor, Jennifer Leight, Biomedical Engineering is a collaborator on this project. Dr. Leight will use her expertise in smart biomaterials to explore mechanical regulation of cellular function as part of the funded work.
Cardiac fibroblasts are the most abundant cell type in the heart and display considerable plasticity, allowing them to adapt to extracellular biochemical and biomechanical signals. Under normal conditions, CFs regulate a dynamic balance between ECM deposition and degradation in order to maintain proper left ventricular structural and mechanical stability. Chronic changes to the mechanical environment alter CF phenotypic thereby contributing to adverse remodeling and heart failure. Volume overload results in increased wall stress and strain as well as elevated levels of pro-fibrotic cytokines. Despite these increases in both mechanical and biochemical stimuli, the heart experiences a net decrease in ECM, which is thought to be a crucial contributor to progression of volume overload heart failure. The proposed work will explore how changes in cyclic strain and tissue stiffness, both mechanical factors known to change during volume overload, impact cardiac fibroblast phenotype with a focus on matrix synthesis and degradation. Since cells respond differently to mechanical stimuli based on the dimensionality of their environment, we will use a 3D culture environment that more accurately reflects the environment of CFs in vivo.
Aim 1. Determine the role of substrate stiffness on the phenotype of CFs cultured in a physiologically relevant 3D environment. Our preliminary data shows that when CFs are cultured as a 2D monolayer, they respond to the stiffness of the material they are cultured on top of with softer substrates promoting a hypo-fibrotic phenotype. A self-assembling peptide gel system will be used study the effects of matrix stiffness on ECM deposition and degradation in 3D cultures.
Aim 2. Determine the effect of cyclic stretch on ECM synthesis and degradation by CFs cultured in a 3D environment at various matrix stiffnesses. Cellular responses to changes in matrix stiffness and cyclic strain will be assessed. We will test the hypothesis that the magnitudes of cytoskeletal tension predicted from in silico models correlate with experimentally measured cellular responses.
Congratulations Drs. Gooch, Lucchesi and Leight!