Regenerative Therapy for Pelvic Organ Prolapse

盆腔器官脱垂的再生治疗

• 批准号: 8769004
• 负责人: MARGOT S. DAMASER
• 金额: $ 23.78万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769004
• 关键词: 3-Dimensional; Accounting; Adult; Affect; Age; Animal Model; Attenuated; Biological Products; Biopsy; Birth; Cells; Child; Clinical; Clinical Trials; Collaborations; Collagen; Correlative Study; Data; Deposition; Development; Dose; Elastic Fiber; Elasticity; Elastin; Elderly woman; Epithelial; Etiology; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Female; Fiber; Fibroblasts; Functional disorder; Future; Goals; Homeostasis; Human; Hyaluronan; Individual; Innovative Therapy; Intervention; Knock-out; Knockout Mice; Lead; Life; Ligaments; Link; Longevity; Mediating; Metric; Monoamine Oxidase; Mus; Muscle; Nanotechnology; Natural regeneration; Operative Surgical Procedures; Organ; Organ Culture Techniques; Outcome; Patients; Pattern; Pelvic floor structure; Pelvis; Peptide Hydrolases; Phase; Pregnancy; Process; Production; Protein-Lysine 6-Oxidase; Proteins; Proteolysis; Ptosis; Quality of life; Risk; Risk Factors; Rubber; Severities; Smooth Muscle Myocytes; Structure; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Extracts; Tissues; Treatment Efficacy; Vagina; Vaginal delivery procedure; Weight-Bearing state; Wild Type Mouse; Woman; Work; base; crosslink; enhancing factor; flexibility; human TGFB1 protein; improved; in vivo; innovation; minimally invasive; mouse model; novel; older women; parity; preclinical study; pregnant; prevent; public health relevance; pup; regenerative; regenerative therapy; repaired; reproductive; resilience; restoration; success; targeted delivery; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Pelvic organ prolapse (POP) reduces the quality of life of many older women in the U.S. There is an unmet need for non-surgical therapies based on POP pathophysiology, to prevent and/or regress this common condition. Towards pioneering the development of such a therapy, we propose an exploratory study to (a) assess aberrations of the structural extracellular matrix (ECM) as a pathophysiological basis for POP and (b) establish proof of concept of an innovative therapeutic strategy based on induced regenerative extracellular matrix repair. Recent data in humans and lysyl oxidase like protein-1 (LOXL1) knockout (KO) suggest that impaired ECM remodeling, particularly that of elastic matrix may be linked to POP. However, it is not known if decreased LOXL1 and aberrations of ECM homeostasis, occur in all POP patients, and if they are a cause of POP or a result of it. Since vaginal wall ECM mechanically supports pelvic floor tissues, restoring homeostasis of vaginal ECM in post-partum pelvic floor tissues may be an effective approach to prevent or reverse POP symptoms even though the clinical etiology may be varied and multifactorial. Elastic matrix does not usually regenerate well in adult tissues and will therefore be our primary target for regenerative therapy, although we will assess restoration of collagen homeostasis as well. We propose to utilize a LOXL1 knockout (KO) mouse model of POP to perform a first phase correlative study to elucidate these mechanistic aspects that, beyond this study, will be useful to assess in vivo therapeutic efficacy of our matrix regenerative approach. We propose two aims to test our hypotheses that LOXL1 deficiency results in aberrations in vaginal ECM assembly & repair after pup delivery, which together with enhanced matrix degradation are associated with POP, and that these aberrations can be attenuated or reversed by induced cellular regenerative ECM repair. Aim 1a. Determine the time course of changes to the homeostasis of structural ECM of the vaginal wall corresponding to POP in LOXL1 KO mice. Aim 1b. Determine how LOXL1 deficiency, pregnancy, vaginal delivery, and prolapse in LOXL1 KO mice, alter new ECM deposition by Non-Epithelial Vaginal Cells (NEVCs). Aim 2. Assess ability of MRFs to restore indicators of structural ECM homeostasis in organ cultures of vaginal wall tissue isolated from LOXL1 KO mice with and without POP. The proposed project builds on an ongoing collaboration and expertise of the co-PIs, Damaser (animal models and POP pathophysiology) and Ramamurthi (ECM regeneration). The study will provide justification, rationale, and feasibility data to continue development of this paradigm-shifting, minimally invasive regenerative therapy with pre-clinical studies in animal models and cultured human vaginal tissue. These in turn will rationalize clinical trials to prevent and/or treat POP towards improvin quality of life for many women. The scientific impact of this study will be improved understanding of the mechanisms of POP development and testing of an innovative therapy for regenerative elastic matrix repair and restoration of ECM homeostasis.

描述（由申请人提供）：盆腔器官脱垂 (POP) 降低了美国许多老年女性的生活质量。基于 POP 病理生理学的非手术治疗来预防和/或逆转这种常见病症的需求尚未得到满足。为了开拓这种疗法的发展，我们提出了一项探索性研究，以（a）评估结构细胞外基质（ECM）的畸变作为 POP 的病理生理学基础，并（b）建立基于诱导再生细胞外基质修复的创新治疗策略的概念证明。最近的人类数据和赖氨酰氧化酶样蛋白 1 (LOXL1) 敲除 (KO) 表明 ECM 重塑受损，尤其是弹性基质重塑可能与 POP 相关。然而，尚不清楚 LOXL1 减少和 ECM 稳态失常是否发生在所有 POP 患者中，以及它们是 POP 的原因还是结果。由于阴道壁 ECM 机械地支撑盆底组织，因此恢复产后盆底组织中阴道 ECM 的稳态可能是预防或逆转 POP 症状的有效方法，尽管临床病因可能多种多样且是多因素的。弹性基质在成人组织中通常不能很好地再生，因此将是我们再生治疗的主要目标，尽管我们也会评估胶原蛋白稳态的恢复。我们建议利用 POP 的 LOXL1 敲除 (KO) 小鼠模型进行第一阶段相关研究，以阐明这些机制方面，除了本研究之外，这些方面将有助于 评估我们的基质再生方法的体内治疗效果。 我们提出两个目标来测试我们的假设，即 LOXL1 缺陷导致幼仔分娩后阴道 ECM 组装和修复的畸变，这与增强的基质降解一起与 POP 相关，并且这些畸变可以通过诱导细胞再生 ECM 修复来减弱或逆转。目标 1a。确定 LOXL1 KO 小鼠中 POP 对应的阴道壁结构 ECM 稳态变化的时间过程。目标 1b。确定 LOXL1 KO 小鼠中 LOXL1 缺陷、妊娠、阴道分娩和脱垂如何改变非上皮阴道细胞 (NEVC) 的新 ECM 沉积。目标 2. 评估 MRF 在从具有和不具有 POP 的 LOXL1 KO 小鼠分离的阴道壁组织的器官培养物中恢复结构 ECM 稳态指标的能力。 拟议的项目建立在联合 PI Damaser（动物模型和 POP 病理生理学）和 Ramamurthi（ECM 再生）的持续合作和专业知识的基础上。该研究将通过动物模型和培养的人类阴道组织的临床前研究，为继续开发这种范式转变的微创再生疗法提供理由、基本原理和可行性数据。这些反过来将使预防和/或治疗 POP 的临床试验合理化，从而改善许多女性的生活质量。这项研究的科学影响将提高对 POP 发展机制的理解，并测试再生弹性基质修复和 ECM 稳态恢复的创新疗法。