Mechanisms and Impact of Pregnancy-Induced Adaptations in Pelvic Floor Muscles

项目摘要 我们的建议证实了NIH的愿景，即临床护理和研究的多学科方法是 在特定领域取得重大进展的最富有成效的范例。虽然 不幸的是，骨骼肌研究的重点是雄性动物模型中的附肢肌 导致女性骨盆骨骼肌领域的临床前研究不足， 针对女性特定疾病（如盆腔炎）的预防或治疗方法的进展 地板障碍;目前的项目建立在肢体中进行的里程碑式研究的发现基础上 肌肉.在这里，我们专注于建立有关女性骨盆底肌肉特异性的基础知识 肌肉干细胞以及怀孕和分娩等关键时期对这些细胞的影响。的 以上是必要的，为未来发展务实的预防方法，以减少病态的影响， 骨盆底疾病对公共卫生的影响。该项目代表了一种新的方法，重点是阐明作用 肌肉干细胞在妊娠诱导的产前适应的骨盆底肌肉以及肌肉 阴道分娩后的再生潜力。为了实现这一目标，我们将使用我们经过验证的实验 一个模型来检查骨盆肌干的表型、功能、转录和表观基因组特征 在妊娠、分娩和产后期间的多个时间点检测细胞，以识别候选信号 调节其功能状态的途径。然后，我们将测试是否暴露于不同方面的前， 和围产期环境调节骨盆肌肉干细胞的再生潜力， 受伤后的肌肉恢复。总的来说，这项创新的研究将提供基本的见解， 参与调节女性盆腔肌肉卫星细胞的生物学过程以及影响其 机械损伤后的再生能力。由此产生的知识将使小说的发展成为可能 预防或治疗女性盆腔肌肉功能障碍的策略。

PROJECT SUMMARY Our proposal exemplifies the NIH vision that the multidisciplinary approach to clinical care and research is the most fruitful paradigm for the development of significant advancements within a specific field. While it is unfortunate that the heavy focus of skeletal muscle research on the appendicular muscles in male animal models led to scarcity of preclinical investigations in the area of female pelvic skeletal muscles and provided little progress toward preventative or therapeutic approaches that target female-specific conditions, such as pelvic floor disorders; the current project builds on the discoveries of the landmark studies conducted in the limb muscles. Here, we focus on building the foundational knowledge pertaining to female pelvic floor muscle -specific muscle stem cells and the impact of such critical time-periods as pregnancy and childbirth on these cells. The above is necessary for future development of pragmatic preventative approaches to reduce the impact of morbid pelvic floor disorders on public health. This project represents a novel approach focused on elucidating the role of muscle stem cells in pregnancy-induced antepartum adaptations of the pelvic floor muscles as well as muscle regenerative potential following vaginal delivery. To achieve this objective, we will use our validated experimental model to examine the phenotypic, functional, transcriptional, and epigenomic signatures of pelvic muscle stem cells at multiple time points across gestation, parturition, and postpartum period to identify candidate signaling pathways regulating their functional state. We will then test whether exposure to different aspects of the ante- and peripartum environment modulates the regenerative potential of pelvic muscle stem cells and impacts muscle recovery following injury. Overall, this innovative study will provide fundamental insights into the biological processes involved in the regulation of female pelvic muscle satellite cells and factors that impact their regenerative capacity following mechanical injury. The resulting knowledge will enable the development of novel strategies to prevent or treat female pelvic muscle dysfunction.