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）：压力性尿失禁 (SUI) 影响大约 35% 的 40 岁以上女性，并带来巨大的社会、医疗和个人负担。 SUI 的发生与怀孕、阴道分娩和衰老密切相关。阴道分娩会导致骨盆底和节制机制损伤；然而，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，分娩创伤后从损伤或缺乏损伤中恢复对于 SUI 的病理生理学同样重要。大约 1/3 的女性在分娩后会出现 SUI，但大多数女性会在一年内消失。随着时间的推移，恢复受损会显着增加 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了解糖尿病或肥胖等促进因素以及衰老等失代偿因素在 SUI 病理生理学中的作用的关键。 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​​了盆腔器官的出生相关创伤，类似于女性胎头通过产道的情况，作为急性可逆损伤模型； b) 糖尿病等失代偿因素会导致 VD 引起的 SUI 的严重程度增加（损伤）并延迟恢复； c) VD后，尿道中单核细胞趋化蛋白-3 (MCP-3)——一种间充质干细胞(MSC)归巢细胞因子——的表达显着增加； d) VD 后静脉输注的 MSC 选择性归巢至尿道与尿道功能加速恢复相关。 在最近的几项流行病学研究中，高龄产妇被认为是产伤后发生 SUI 的一个可能的危险因素。这些观察结果具有重大的临床和社会意义，因为它们旨在回答以下问题：阴道分娩后发生 SUI 的风险是否证明建议进行初次选择性剖腹产，特别是对于 30 岁以上第一次怀孕的母亲。 因此，在本申请中，我假设 SUI 的发展是两个相互作用过程之间不平衡的结果：1）损伤 - 与分娩相关的下尿路和盆底组织创伤；2）恢复能力使受伤的组织从出生创伤中恢复。我进一步假设恢复与损伤后尿道中归巢因子局部表达继发的干细胞动员密切相关。我将研究衰老对这条途径的影响。选择老化模型作为“恢复受损”的模型。 为了检验这些假设，我计划进行两类实验：1）通过功能性渗漏点压力（LPP）、形态测量结果和旁分泌表达来测量年轻可育小鼠、老年可育小鼠和老年小鼠的损伤恢复模式。节制机制（尿道）微环境的因素； 2) 使用相似的结果测量，检查静脉注射人间充质干细胞 (hMSC) 对同一组小鼠 VD 诱导的 SUI 恢复的治疗影响。这种机制是一个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治疗选择。 公共健康相关性：压力性尿失禁 (SUI) 带来巨大的社会、医疗和个人负担。 SUI 的发生与妊娠、产妇年龄、阴道分娩和衰老密切相关。本研究旨在了解介导损伤与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。