Targeted Regenerative Therapy For Urinary Incontinence

尿失禁的靶向再生治疗

• 批准号: 10019164
• 负责人: James Koudy Williams
• 金额: $ 26万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019164
• 关键词: Abdomen; Address; Adrenergic Agents; Aging; Anatomy; Animal Model; Animals; Apoptosis; Architecture; Bladder; Blood Vessels; Blood flow; Bone Marrow Cells; Bone Marrow Transplantation; CXCL12 gene; CXCR4 Receptors; Cell Proliferation; Cell Therapy; Cells; Cellular Structures; Childbirth; Chronic; Clinical Research; Collagen; Complex; Cytoskeleton; Data; Data Reporting; Detection; Development; Devices; Disease; Elastin; Extravasation; Financial Hardship; Frequencies; Functional disorder; Gap Junctions; Human; Impairment; Incontinence; Individual; Injections; Injury; Label; Lower urinary tract; Measures; Mediating; Menarche; Menopause; Microspheres; Modeling; Muscle; Natural regeneration; Nerve; Normal tissue morphology; Operative Surgical Procedures; Patients; Pattern; Pelvic floor structure; Posture; Premenopause; Prevalence; Process; Production; Publishing; Quality of life; Reporting; Rest; Risk; Role; Smooth Muscle; Societies; Sphincter; Stress Urinary Incontinence; Striated Muscles; Structure; Syndrome; Testing; Time; Tissues; Treatment Cost; Treatment Efficacy; Urethra; Urinary Incontinence; Urination; Urine; Urodynamics; Urologic Diseases; Vascularization; Wireless Technology; Woman; chemokine; chemokine therapy; clinical translation; experimental study; interest; muscle regeneration; nerve supply; nonhuman primate; novel; older women; pressure; regenerative; regenerative therapy; reproductive; tissue regeneration; urinary; urologic

Urinary sphincter deficiency (ISD) is associated with stress urinary incontinence (SUI) in women and remains a major urological problem. Although good results of surgical therapy for SUI/ISD have been reported, complications are not infrequent, requiring almost 1/3 of patients requiring a second surgery and alternatives are needed. This has increased interest in cell therapy approaches to restore sphincter function. However, results of clinical studies using regenerative cell therapy have been only modest, with an average of 50% beneficial effects in around 50% of patients. As an alternative to cell therapy, this study will focus on the use of targeted chemokine CXCL12 (C-X-C motif chemokine 12) treatment for SUI/ISD using our established nonhuman primate (NHP) model of chronic ISD. The rationale for using CXCL12 is our published preliminary data reporting that local injection of CXCL12, but not cell therapy, restored urinary sphincter structure and function in the NHPs with chronic ISD. While these experiments provided proof-of-principle for this treatment approach, proposed experiments will not confirm and greatly expand this finding by exploring the mechanism underlying these beneficial effects. In addition, we will better define long-term functionality by assessing sphincter function and structure at increasing time points after injection. Proposed experiments will test the hypothesis that CXCL12-mediated cell mobilization to the urinary sphincter is a major underlying mechanism contributing to long-term regeneration of urinary sphincter structure and function in this LUTD. To address this hypothesis, we propose an in-depth assessment of the time-course changes in sphincter cell and matrix cellular and matrix composition for up to 12 months following local CXCL12 injections into the urinary sphincter of NHPs with chronic ISD. The aims are: 1) To assess the time-course effects of local CXCL12 injection on the cellular and structural development of the urinary sphincter. We will use novel multiplex/multispectral analysis of the urinary sphincter complex to test our working hypothesis that, after partial bone marrow transplantation with lenti-GFP transduced BMCs, CXCL12 will stimulate mobilization of GFP-BMCs to the urinary sphincter complex and that these cells provide continued production of chemokines associated with sustained nerve, vascular, muscle regeneration with native tissue-like architecture; and 2) To measure the time-course effects of CXCL12 on sphincter function. We will perform urodynamic measures resting and nerve-stimulated sphincter and bladder pressures, and quantify micturition patterns as functional correlates to the structural effects of CXCL12 therapy (Aim 1) to test our hypothesis that CXCL12 restores functional muscle and innervation that support innervated sphincter pressures; resting and nerve-stimulated sphincter blood flow; and normal micturition patterns. It is anticipated that this study will provide new data about a targeted chemokine therapy for late pre-menopausal chronic ISD. It will also provide new information about the cell mobilization capabilities of CXCL12, how these mobilized cells contribute to tissue regeneration and the long-term efficacy of this therapeutic approach.

尿括约肌缺乏（ISD）与女性的压力尿失禁（SUI）有关，并且仍然是 主要的泌尿外科问题。尽管已经报道了SUI/ISD手术疗法的良好结果，但 并发症并不罕见，需要将近1/3的患者需要进行第二次手术和替代方案 需要。这增加了对恢复括约肌功能的细胞疗法方法的兴趣。然而， 使用再生细胞疗法的临床研究结果仅适度，平均为50％ 大约50％的患者有益影响。作为细胞疗法的替代方案，本研究将重点介绍 使用我们已建立的非人类 慢性ISD的灵长类动物（NHP）模型。使用CXCL12的理由是我们已发布的初步数据 报告报告局部注入CXCL12但没有细胞疗法，恢复了尿括约肌结构和功能 在NHP中，具有慢性ISD。尽管这些实验为这种治疗方法提供了原理证明，但 提出的实验不会通过探索基础机制来确认并大大扩展这一发现 这些有益的效果。此外，我们将通过评估括约肌来更好地定义长期功能 和注射后时间点增加的结构。提出的实验将检验以下假设 CXCL12介导的细胞动员向泌尿括约肌动员是一种主要的潜在机制，有助于 该LUTD中尿括约肌结构和功能的长期再生。为了解决这一假设，我们 提出对括约肌和基质细胞和基质的时间课程变化的深入评估 局部CXCL12注射到NHP的尿括约肌后，最多12个月的成分 慢性ISD。目的是：1）评估局部CXCL12注入对细胞的时间课程影响 和泌尿括约肌的结构发展。我们将使用新颖的多重/多光谱分析 尿括约肌复合物测试我们的工作假设，在部分骨髓移植后 Lenti-GFP转导的BMC，CXCL12将刺激GFP-BMC的动员向尿括约肌 复合物，这些细胞提供与持续神经相关的趋化因子的持续产生， 具有天然组织样结构的血管，肌肉再生； 2）衡量时间课程效果 CXCL12在括约肌功能上的of。我们将进行尿动力学措施休息和神经刺激 括约肌和膀胱压力，并将排尿模式定量与结构相关 CXCL12治疗的影响（目标1）测试我们的假设CXCL12恢复功能性肌肉和 支配支配括约肌压力的神经；静止和神经刺激的括约肌血流；和 正常的排尿模式。预计这项研究将提供有关靶向趋化因子的新数据 疗程晚期慢性慢性ISD。它还将提供有关细胞动员的新信息 CXCL12的能力，这些动员细胞如何促进组织再生和长期疗效 这种治疗方法。