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.

尿括约肌缺乏症(ISD)与女性压力性尿失禁(SUI)有关，仍是一种 严重的泌尿科问题。尽管手术治疗SUI/ISD的良好效果已有报道， 并发症并不少见，几乎三分之一的患者需要二次手术和其他选择 都是需要的。这增加了人们对恢复括约肌功能的细胞疗法的兴趣。然而， 使用再生细胞疗法的临床研究结果并不明显，平均为50%。 对大约50%的患者有好处。作为细胞治疗的替代方案，这项研究将重点放在使用 靶向趋化因子CXCL12(C-X-C基序趋化因子12)治疗SUI/ISD 慢性ISD灵长类动物(NHP)模型。使用CXCL12的基本原理是我们发布的初步数据 报道称，局部注射CXCL12，而不是细胞疗法，恢复了尿括约肌的结构和功能 在有慢性ISD的NHP中。虽然这些实验为这种治疗方法提供了原则上的证据， 拟议中的实验不会通过探索潜在的机制来证实和大大扩展这一发现 这些有益的影响。此外，我们将通过评估括约肌功能来更好地定义长期功能 以及注射后增加时间点的结构。拟议中的实验将检验这一假设 CXCL12介导的细胞对尿括约肌的动员是导致尿失禁的主要潜在机制 LUTD患者尿括约肌结构和功能的长期再生。为了解决这一假设，我们 提出对括约肌细胞、基质细胞和基质随时间变化的深入评估 将CXCL12局部注射到NHP的尿括约肌后12个月内的成分 慢性间歇性胰腺炎。其目的是：1)评估局部注射CXCL12对细胞的时程影响 以及尿括约肌的结构发育。我们将使用新的多路/多光谱分析 尿括约肌复合体来验证我们的工作假设，在部分骨髓移植后 Lenti-GFP转导的BMCs，CXCL12将刺激GFP-BMCs动员到尿括约肌 这些细胞提供持续产生与持续神经相关的趋化因子， 血管、肌肉再生和天然组织样结构；以及2)测量时间进程的影响 CXCL12对括约肌功能的影响。我们将进行休息和神经刺激的尿动力学测量 括约肌和膀胱压力，并量化排尿模式作为功能相关的结构性 CXCL12治疗的效果(目标1)以验证我们的假设，即CXCL12恢复功能肌肉和 支持神经性括约肌压力的神经支配；静息和神经刺激的括约肌血流； 正常排尿模式。预计这项研究将提供有关靶向趋化因子的新数据 绝经前晚期慢性胰岛素依赖症的治疗。它还将提供有关细胞动员的新信息 CXCL12的功能，这些动员的细胞如何促进组织再生和长期疗效 这种治疗方法。