Architectural Design of the Pelvic Floor Skeletal Muscles

描述(申请人提供)：盆底疾病(PFD)包括盆腔器官脱垂(POP)、尿失禁和大便失禁。她们对女性的影响是巨大的，导致骨盆疼痛、性功能障碍、社会孤立、抑郁和糟糕的身体形象。PFD的病因是多因素和复杂的，阴道分娩被认为是其发展的主要危险因素。限制在确定PFD确切原因方面取得进展的关键障碍是我们对导致盆底功能障碍的基本机制缺乏了解。影像和模型研究提供了充分的证据表明，骨骼肌是盆底支持的重要因素，并受到阴道BIRT的有害影响，但这些报告并未以机械性方式与阴道分娩、盆底肌肉损伤和PFD之间存在因果联系。这一重大的知识差距使制定有效的预防措施和/或治疗PFD变得困难。为了确定盆底横纹肌功能与PFD的潜在联系机制，将量化肌肉结构及其细胞外基质(ECM)的特性。这将使我们能够阐明这些肌肉中的结构-功能关系。在骨科领域，一旦建立了精确的肌肉结构、生理学和病理生理学，肌肉功能障碍的治疗就可能取得重大进展。类似的飞跃对于实现女性骨盆医学的进步至关重要。在这项提案中，我们将定义未分娩和临产女性身体的盆底肌肉的结构和肌肉内ECM，以了解这些肌肉的设计和功能的细节，使它们能够发挥复杂的双重作用：支持盆腔内脏和帮助控制大小便，以及促进排尿、排便和分娩。我们假设单个盆底肌肉的结构和ECM是不同的，以允许在盆底扮演特殊的角色。单独的盆底肌肉因阴道分娩而可变但永久地改变，这损害了它们的功能。这些变化对生物力学特性产生负面影响，并在以后的生活中导致盆底功能障碍的发展。这些研究的结果将提高我们对导致盆底肌肉从生理性重塑向病理性重塑转变的事件的理解，并将对开发有效的策略来避免或延迟PFD具有重要意义。我们研究中使用的跨学科方法将对这些极少被研究的疾病产生重大影响，这些疾病对世界各地数百万妇女的生活产生了负面影响。

DESCRIPTION (provided by applicant): Pelvic floor disorders (PFD) include pelvic organ prolapse (POP), urinary incontinence, and fecal incontinence. Their impact on women is significant, causing pelvic pain, sexual dysfunction, social isolation, depression, and poor body image. PFD etiology is multifactorial and complex, with vaginal delivery identified as the leading risk factor for its development. The critical barrier that limits progress in identifying the precie cause of PFD is our lack of understanding of fundamental mechanisms that lead to pelvic floor dysfunction. Imaging and modeling studies have provided ample evidence that skeletal muscles are substantial contributors to pelvic floor support and are deleteriously affected by vaginal birt, but these reports have not causally linked vaginal birth, pelvic floor muscles' injury, and PFD in a mechanistic fashion. This significant knowledge gap makes it difficult to cultivate effective preventive measures and/or treatments for PFD. To define a potential mechanism that links pelvic floor striated muscle function and PFD, muscle architecture and the properties of its extracellular matrix (ECM) will be quantified. This will allow us to elucidate the structure-functin relationships in these muscles. In the field of orthopedics, significant advances in the treatment of muscular dysfunction became possible once precise muscles' structure, physiology and pathophysiology were established. An analogous leap forward is essential for progress to be realized in female pelvic medicine. In this proposal, we will define the architecture and intramuscular ECM of pelvic floor muscles from nulliparous and parous female human cadavers in order to understand specifics of these muscles' design and function that allow them to serve a complex dual role: provide support to the pelvic viscera and aid in continence, as well as facilitate urination, defecation, and parturition. We hypothesize that individual pelvic floor muscles' architecture and ECM are differentiated to allow for specialized roles in the pelvic floor Individual pelvic floor muscles are variably but permanently altered by vaginal deliveries, which compromises their function. These changes negatively impact biomechanical properties and contribute to the development of pelvic floor dysfunction later in life. The results of these studis will improve our understanding of events that cause pelvic floor muscles to switch from physiological to pathological remodeling and will have major implications in developing effective strategies for averting or delaying PFD. The interdisciplinary approach used in our research will have a significant impact on these vastly understudied conditions that negatively affect the lives of millions of women world-wide.