Architectural Design of the Pelvic Floor Skeletal Muscles

描述（由申请人提供）：盆底疾病（PFD）包括盆腔器官脱垂（POP）、尿失禁和大便失禁。它们对女性的影响很大，会导致盆腔疼痛、性功能障碍、社交孤立、抑郁和身体形象不佳。PFD的病因是多因素和复杂的，阴道分娩被确定为其发展的主要危险因素。限制确定PFD确切病因进展的关键障碍是我们缺乏对导致盆底功能障碍的基本机制的理解。影像学和模型研究提供了充分的证据，表明骨骼肌是骨盆底支撑的重要组成部分，并且受到阴道分娩的有害影响，但这些报告并没有将阴道分娩、骨盆底肌肉损伤和PFD在机械方式上联系起来。这一重大的知识差距使得很难培养有效的PFD预防措施和/或治疗方法。为了确定骨盆底横纹肌功能与PFD之间的潜在机制，将对肌肉结构及其细胞外基质（ECM）的特性进行量化。这将使我们能够阐明这些肌肉的结构-功能关系。在骨科领域，一旦建立了精确的肌肉结构、生理和病理生理，肌肉功能障碍的治疗就有可能取得重大进展。类似的飞跃对于女性盆腔医学的进步是必不可少的。在本提案中，我们将定义骨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：为盆腔脏器提供支持，帮助控制，以及促进排尿，排便和分娩。我们假设个体盆底肌肉的结构和ECM是不同的，以允许盆底的特殊作用，个体盆底肌肉是可变的，但永久改变阴道分娩，这损害了他们的功能。这些变化会对生物力学特性产生负面影响，并导致骨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转向病理性重塑的事件的理解，并将对制定避免或延迟PFD的有效策略具有重要意义。我们研究中使用的跨学科方法将对这些对全世界数百万妇女的生活产生负面影响的尚未充分研究的情况产生重大影响。

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.