Tissue recovery in the pathophysiology of stress urinary incontinence

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的发生与妊娠、阴道分娩和衰老密切相关。阴道分娩导致骨盆底和尿道机制的损伤;然而，损伤本身并不能解释SUI病理生理机制的全貌。临床和实验数据表明，分娩创伤后从损伤或缺乏损伤中恢复对SUI的病理生理学同样重要。大约三分之一的妇女在分娩后发展为SUI，但大多数妇女在一年内解决。随着时间的推移，恢复受损会显著增加SUI复发的机会。了解介导损伤和恢复之间平衡的机制似乎是理解促进因素（如糖尿病或肥胖）和失代偿因素（如衰老）在SUI病理生理学中的作用的关键。 我们和其他研究人员已经使用动物模型来研究SUI的机制。这些研究已经表明a）SUI的阴道扩张（VD）模型模拟了与分娩相关的对骨盆器官的创伤，类似于妇女中胎儿头部通过产道的情况，作为急性可逆损伤模型; B）失代偿因素如糖尿病引起VD诱导的SUI的严重程度（损伤）增加和恢复延迟; c）VD后，单核细胞趋化蛋白-3（MCP-3）-间充质干细胞（MSC）归巢细胞因子-在尿道中的表达显著增加;和d）VD后静脉输注的MSC选择性归巢至尿道与尿道的加速功能恢复相关。 在最近的几项流行病学研究中，据报道，高龄产妇是产伤后发生SUI的一个合理风险因素。这些观察结果具有重大的临床和社会意义，因为它们建议回答以下问题：阴道分娩后发生SUI的风险是否证明了初次选择性剖腹产的建议是合理的，特别是在30岁以上首次妊娠的母亲中。 因此，在本申请中，我假设SUI的发展是两个相互作用的过程之间不平衡的结果：1）损伤-来自分娩相关的对下尿路和骨盆底组织的创伤，以及2）恢复-损伤组织从分娩创伤损伤中恢复的能力。我进一步假设，恢复是密切相关的动员干细胞继发于局部表达的归巢因子在尿道损伤后。我将研究衰老对这一途径的影响。老化模型被选为“受损恢复”的模型。 为了验证这些假设，我计划进行两条线的实验：1）通过测量功能性漏点压（LPP）、形态测量结果和尿道微环境（尿道）中旁分泌因子的表达来确定年轻生育小鼠、老年生育小鼠和老年小鼠从损伤中的不同恢复模式; 2）使用类似的结果测量来检查静脉内注射的人间充质干细胞（hMSC）在同一组小鼠中恢复VD诱导的SUI中的治疗影响。这种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切适用的治疗选择。 公共卫生相关性：应激性尿失禁（SUI）带来了巨大的社会、医疗和个人负担。SUI的发生与妊娠、母亲年龄、阴道分娩和衰老密切相关。本研究旨在了解介导损伤和恢复之间平衡的机制以及间充质干细胞在恢复中的作用，并评估衰老对干细胞治疗的平衡和反应的影响。

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.