Tissue recovery in the pathophysiology of stress urinary incontinence

描述(申请人提供)：压力性尿失禁(SUI)影响大约35%的40岁以上的女性，并带来巨大的社会、医疗和个人负担。SUI的发生与怀孕、阴道分娩和年龄增长密切相关。阴道分娩会导致盆底和大小便失禁机制的损伤；然而，损伤本身并不能解释SUI的病理生理机制的全部情况。临床和实验数据表明，分娩创伤后损伤或缺失的恢复对SUI的病理生理学具有同样重要的意义。大约三分之一的妇女在分娩后出现SUI，但在大多数妇女中，这一问题在一年内就会解决。随着时间的推移，康复受损会显著增加SUI的复发机会。了解损伤与恢复之间的平衡机制似乎是理解糖尿病或肥胖等促进因素以及衰老等失代偿因素在SUI病理生理中的作用的关键。我们和其他研究人员使用动物模型来研究SUI的机制。这些研究表明，a)SUI的阴道扩张(VD)模型模拟了与分娩有关的盆腔器官损伤，类似于女性胎头通过产道的急性可逆损伤模型；b)糖尿病等失代偿因素导致严重程度(损伤)增加和VD导致的SUI恢复延迟；c)VD后，单核细胞趋化蛋白-3(MCP-3)-一种间充质干细胞(MSC)归巢细胞-在尿路中的表达显著增加；以及d)VD后选择性地将MSCs回输到尿路与加速尿路功能恢复有关。在最近的几项流行病学研究中，高龄产妇被报告为产后创伤后发生SUI的一个合理的危险因素。这些观察具有重大的临床和社会意义，因为他们建议回答这样一个问题，即阴道分娩后发生SUI的风险是否证明推荐初级选择性剖宫产是合理的，特别是在首次怀孕的30岁以上的母亲中。因此，在这一应用中，我假设SUI的发展是两个相互作用过程之间失衡/平衡的结果：1)损伤--从与分娩有关的创伤到下尿路和盆底组织，以及2)损伤组织从出生创伤损伤中恢复的能力。我进一步假设，康复与干细胞的动员密切相关，继而在损伤后的尿路中局部表达归巢因子。我将研究衰老对这一途径的影响。衰老模型被选为“恢复受损”的模型。为了验证这些假设，我计划进行两项实验：1)通过测量功能渗漏点压(LPP)、形态计量学结果以及旁分泌因子在可控机制微环境(尿路)中的表达，确定年轻能育小鼠、老年能育小鼠和老龄小鼠损伤后的不同恢复模式；2)采用类似的结果测量方法，检测静脉注射人间充质干细胞(HMSCs)对同一组小鼠VD所致SUI的治疗作用。这一机制是一种非常令人兴奋的机制，因为它为我们和科学界提供了迫在眉睫的适用治疗选择。 公共卫生相关性：压力性尿失禁(SUI)给社会、医疗和个人带来巨大的负担。SUI的发生与怀孕、产妇年龄、阴道分娩和年龄密切相关。本研究旨在了解间充质干细胞调节损伤与恢复平衡的机制以及间充质干细胞在恢复中的作用，并评价衰老对干细胞治疗平衡和反应的影响。

DESCRIPTION (provided by applicant): Stress urinary incontinence (SUI) affects approximately 35% of women over the age of 40 and carries a large social, medical and personal burden. Development of SUI is strongly associated with pregnancy, vaginal delivery and aging. Vaginal delivery results in injury to the pelvic floor and continence mechanism; however, injury alone does not explain the entire picture on the pathophysiological mechanisms of SUI. Clinical and experimental data suggest that recovery from the injury or lack thereof, following childbirth trauma is as significant to the pathophysiology of SUI. Approximately 1/3 of women develop SUI following delivery but in most women this resolves within a year. Impaired recovery significantly increases the chance of recurrence of SUI over time. Understanding the mechanisms mediating the balance between injury and recovery appear to be the key in understanding the role of promoting factors such as diabetes or obesity, and decompensating factors such as aging in the pathophysiology of SUI. We, and other investigators, have used animal models to investigate the mechanisms of SUI. These investigations have shown that a) vaginal distension (VD) models of SUI simulate the birth related trauma to the pelvic organs similar to the passage of the fetal head through the birth canal in women as an acute reversible model of injury; b) decompensating factors such as diabetes mellitus causes both increased severity (injury) and delayed recovery from VD induced SUI; c) following VD, expression of monocyte chemotactic protein-3 (MCP-3)- a mesenchymal stem cell (MSC) homing cytokine- is dramatically increased in the urethra; and d) selective homing of intravenously infused MSCs to the urethra following VD is associated with an accelerated functional recovery of the urethra. In several recent epidemiological studies, advanced maternal age has been reported as a plausible risk factor for development of SUI following birth trauma. These observations have MAJOR clinical and social implications as they propose to answer the question of whether risk of development of SUI following vaginal delivery justifies the recommendation for primary elective C-section, especially in mothers who are older than age of 30 with their 1st pregnancy. Thus, in this application I hypothesize that the development of SUI is the result of im/balance between two interacting processes: 1)Injury- from child birth related trauma to the tissues of the lower urinary tract and pelvic floor and 2)Recovery- ability of the injured tissues to recover from birth trauma injury. I further hypothesize that recovery is intimately related to the mobilization of stem cells secondary to local expression of homing factors in the urethra following injury. I will investigate the impact of aging on this pathway. Aging model is chosen as a model for 'impaired recovery'. To test these hypotheses, I plan to carry out 2 lines of experiments: 1) to determine differential recovery patterns from injury in young fertile, old fertile and aged mice as measured by functional leak point pressure(LPP), morphometric outcomes and expression of paracrine factors in the micro environment of the continence mechanisms (urethra); 2) to examine the therapeutic impact of intravenously injected human mesenchymal stem cells (hMSCs) in recovery of VD- induced SUI in the same group of mice using similar outcome measures. This mechanism is a very exciting mechanism as it provides us and the scientific community with imminently applicable therapeutic options. PUBLIC HEALTH RELEVANCE: Stress Urinary Incontinence (SUI) presents a large social, medical and personal burden. Development of SUI is strongly associated with pregnancy, maternal age, vaginal delivery and aging. This study is directed at understanding the mechanisms mediating the balance between injury and recovery and the role of mesenchymal stem cells in recovery and to evaluate the effect of aging on the balance and response to stem cell therapy.