This Faculty Early Career Development (CAREER) grant will investigate how the smooth muscle cells in the uterus respond and adapt to mechanical forces. The uterus is a muscular organ that contracts due to the shortening of smooth muscle cells located in its wall. Pregnancy and many uterine disorders, such as fibroids, change the mechanical load on uterine smooth muscle cells. However, the effects of mechanical forces on uterine smooth muscle cells are poorly understood. This fundamental science gap in understanding hinders the development of treatment strategies for uterine disorders. For example, during pregnancy, uterine smooth muscle cells are stretched by the growing fetus but remain quiescent until the fetus reaches term, at which point they rapidly become contractile. If this transition occurs too early, this can result in preterm labor and birth. Preterm birth is the leading cause of neonatal death in the US. It is difficult to predict or prevent in large part because the biomechanical and biochemical stimuli that trigger uterine contractions are poorly understood. Given these knowledge gaps, the research goal of this project is to measure how the contractility of uterine smooth muscle cells is affected by tissue stiffening and stretch. A second goal is to identify the mechanosensing proteins and pathways inside uterine smooth muscle cells. These could be leveraged as therapeutic targets for conditions such as preterm labor or fibroids. The major educational goal of this project is to develop a series of interactive hands-on activities related to muscle mechanobiology and tissue engineering for high school students. These activities will be developed in partnership with undergraduate student volunteers, executed at a local high school in urban Los Angeles, and broadly disseminated.
The specific research goal of this project is to establish new insights into the mechanobiology of human uterine smooth muscle cells using engineered cell and tissue models. First, the effects of matrix rigidity on calcium activity, contractility, and gene expression in engineered human uterine smooth muscle microtissues will be measured. Second, the independent and combined effects of mechanical stretch and progesterone (the pregnancy hormone) on contractility, mechanoadaptation, and gene expression in engineered human uterine smooth muscle microtissues will be measured. Third, molecules expected to be mechanosensors will be perturbed and sensitivity to matrix rigidity and stretch will be re-evaluated to identify mechanisms of mechanosensing. With tightly coupled educational objectives to broaden participation, this project will also positively impact the career trajectory of the PI by supporting the pursuit of a new research direction on an important topic.
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.
