CAREER: Establishing New Insights into Uterine Smooth Muscle Cell Mechanobiology with Engineered Tissue Models

这项学院早期职业发展(Career)补助金将研究子宫中的平滑肌细胞如何对机械力做出反应和适应。子宫是一个肌肉器官，由于其壁上的平滑肌细胞缩短而收缩。怀孕和许多子宫疾病，如子宫肌瘤，会改变子宫平滑肌细胞的机械负荷。然而，机械力对子宫平滑肌细胞的影响还知之甚少。这一认识上的基础科学鸿沟阻碍了子宫疾病治疗策略的发展。例如，在怀孕期间，子宫平滑肌细胞被发育中的胎儿拉伸，但保持静止，直到胎儿到达足月，在这一点上它们迅速收缩。如果这种转变发生得太早，可能会导致早产和分娩。在美国，早产是新生儿死亡的主要原因。很难预测或预防，很大程度上是因为人们对引发子宫收缩的生物力学和生化刺激知之甚少。鉴于这些知识差距，这个项目的研究目标是测量子宫平滑肌细胞的收缩能力如何受到组织僵硬和拉伸的影响。第二个目标是确定子宫平滑肌细胞内的机械感应蛋白质和途径。这些可以作为早产或子宫肌瘤等疾病的治疗靶点。该项目的主要教育目标是为高中生开发一系列与肌肉机械生物学和组织工程相关的互动动手活动。这些活动将与本科生志愿者合作开发，在洛杉矶市区的一所当地高中执行，并广泛传播。该项目的具体研究目标是利用工程细胞和组织模型对人类子宫平滑肌细胞的机械生物学建立新的见解。首先，将测量基质刚性对工程化人子宫平滑肌微组织中钙活性、收缩能力和基因表达的影响。其次，将测量机械拉伸和孕酮(孕激素)对工程化人子宫平滑肌微组织的收缩、机械适应和基因表达的独立和联合影响。第三，被认为是机械传感器的分子将被扰动，对基质刚性和拉伸的敏感性将被重新评估，以确定机械传感器的机制。随着教育目标的紧密结合以扩大参与，该项目还将通过支持在重要主题上追求新的研究方向来积极影响PI的职业发展轨迹。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.