Tissue recovery in the pathophysiology of stress urinary incontinence

压力性尿失禁病理生理学中的组织恢复

• 批准号: 8029153
• 负责人: Adonis K Hijaz
• 金额: $ 14.85万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8029153
• 关键词: Acute; Affect; Age; Aging; Animal Model; Apoptotic; Birth; Birth trauma; CXCR4 gene; Chemokine (C-C Motif) Receptor 1; Child; Childbirth; Clinical; Communities; Coughing; Data; Development; Diabetes Mellitus; E-Selectin; Elderly woman; Environment; Epidemiologic Studies; Equilibrium; Evaluation; Exertion; Extravasation; Female; Functional disorder; Future; Generations; Genetic; Head; Hematopoietic Stem Cell Mobilization; Homing; Human; Inflammatory; Injection of therapeutic agent; Injury; Insulin-Like Growth Factor I; Interferons; Interleukin-2; Investigation; Ischemia; Lower urinary tract; Maternal Age; Measurable; Measures; Mediating; Medical; Mesenchymal Stem Cells; Modeling; Mothers; Mus; Obesity; Organ; Outcome; Outcome Measure; Pathway interactions; Pattern; Pelvic floor structure; Pelvis; Play; Postpartum Women; Pregnancy; Prevalence; Process; Rattus; Recommendation; Recovery; Recovery of Function; Recurrence; Reporting; Research Personnel; Risk; Risk Factors; Role; Secondary to; Severities; Signal Transduction; Simulate; Sneezing; Stem cells; Stress Urinary Incontinence; Stromal Cell-Derived Factor 1; Testing; Therapeutic; Time; Tissues; Trauma; Urethra; Urinary Incontinence; Urine; Vagina; Vaginal delivery procedure; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factors; Woman; Wood material; advanced maternal age; age effect; aged; cytokine; fetal; high risk; injured; migration; monocyte chemoattractant protein-3; paracrine; pressure; prospective; receptor; research study; response; social; social implication; stem cell therapy

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.

描述（由申请人提供）：压力尿失禁（SUI）影响了40岁以上约35％的妇女，并承担着巨大的社会，医疗和个人负担。 SUI的发展与妊娠，阴道分娩和衰老密切相关。阴道递送导致骨盆底和连续性机制受伤；但是，仅损伤并不能解释SUI病理生理机制的全部情况。临床和实验数据表明，在分娩后，从损伤中恢复或缺乏损伤，对SUI的病理生理学同样重要。分娩后大约有1/3的妇女发展SUI，但在大多数女性中，这在一年内就可以解决。随着时间的推移，恢复障碍大大增加了SUI复发的机会。了解介导伤害和康复之间平衡的机制似乎是理解促进糖尿病或肥胖等因素的作用的关键，以及诸如SUI病理生理学中衰老等因素的代偿因素。 我们和其他研究人员已经使用动物模型来研究SUI的机制。这些研究表明，a）SUI的阴道扩张（VD）模型模拟​​了与骨盆器官的出生相关创伤，类似于胎儿头部通过女性穿过出生管的通过，作为急性逆转损伤模型； b）糖尿病等代偿因素会导致严重程度增加（损伤）和VD诱导的SUI恢复的延迟； c）VD之后，单核细胞趋化蛋白-3（MCP-3）的表达 - 尿道中的间充质干细胞（MSC）归巢细胞因子 - 在尿道中显着增加； d）在VD之后，静脉注入的MSC选择性归巢与尿道的功能恢复有关。 在最近的一些流行病学研究中，据报道，高级产妇年龄是出生创伤后SUI发展的合理危险因素。这些观察结果具有重大的临床和社会意义，因为它们建议回答阴道分娩后SUI的风险是否形成的问题证明对初级选修课的建议是合理的，尤其是在第一次怀孕的30岁以上的母亲中。 因此，在这项应用中，我假设SUI的发展是两个相互作用过程之间IM/平衡的结果：1）受伤 - 从与儿童相关的创伤到下尿路和骨盆底的组织，以及2）受伤的组织的恢复能力从出生创伤损伤中恢复。我进一步假设，恢复与受伤后尿道因子局部表达继发于局部表达的干细胞密切相关。我将研究衰老对这一途径的影响。选择老化模型作为“恢复受损”的模型。 为了检验这些假设，我计划进行2行实验：1）确定通过功能性泄漏点压力（LPP）测量的年轻肥沃，肥沃和年龄小鼠损伤的差异恢复模式，形态计量结果和旁分泌因子在恒定机制微环境中（Urethra）的表达； 2）使用类似的结果指标，检查了静脉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即将适用的治疗选择。 公共卫生相关性：压力尿失禁（SUI）带来了巨大的社会，医疗和个人负担。 SUI的发展与妊娠，产妇年龄，阴道分娩和衰老密切相关。这项研究旨在了解介导损伤与恢复之间的平衡以及间充质干细胞在恢复中的作用的机制，并评估衰老对干细胞疗法的平衡和反应的影响。