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

职业：利用工程组织模型建立对子宫平滑肌细胞力学生物学的新见解

基本信息

批准号：
1944734
负责人：
Megan McCain
金额：
$ 50万
依托单位：
University of Southern California
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1944734&HistoricalAwards=false
关键词：
CAREER Establishing New Insights into

项目摘要

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.

这位教师早期职业发展（职业）格兰特将调查子宫中的平滑肌细胞如何反应并适应机械力。子宫是一种肌肉器官，由于位于其壁上的平滑肌细胞缩短而导致收缩。妊娠和许多子宫疾病，例如肌瘤，改变了子宫平滑肌细胞的机械负荷。但是，机械力对子宫平滑肌细胞的影响知之甚少。理解的这种基本科学差距阻碍了子宫疾病的治疗策略的发展。例如，在怀孕期间，子宫平滑肌细胞被增长的胎儿拉伸，但保持静止，直到胎儿达到期限为止，此时它们迅速成为收缩。如果这种过渡发生得为时过早，则可能导致早产和出生。早产是美国新生儿死亡的主要原因。很难在很大程度上预测或预防，因为触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，该项目的研究目标是衡量子宫平滑肌细胞的收缩力如何受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敏蛋白和途径。这些可以用作早产或肌瘤等疾病的治疗靶标。该项目的主要教育目标是开发一系列与高中生的肌肉机械生物学和组织工程有关的互动动手活动。这些活动将与本科生志愿者合作开发，并在洛杉矶城市的一所当地高中处决，并广泛传播。该项目的具体研究目标是使用工程细胞和组织模型对人子宫平滑肌细胞的机械生物学建立新的见解。首先，将测量基质刚性对钙活性，收缩力和基因表达在工程人子宫平滑肌微动物中的影响。其次，将测量机械拉伸和孕酮（妊娠激素）对工程人子宫平滑肌微动物中收缩力，机械加热和基因表达的独立和组合作用。第三，预计将是机械传感器的分子将受到干扰，并且对基质刚度和拉伸的敏感性将被重新评估以识别机械传感的机制。通过紧密耦合的教育目标以扩大参与，该项目还将通过支持对重要主题的新研究方向的追求新的研究方向，从而对PI的职业发展进行积极影响。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的智力和更广泛影响的评估来通过评估来支持的，这是值得的。