Targeted Regenerative Therapy For Urinary Incontinence

尿道括约肌功能不全（ISD）与女性压力性尿失禁（SUI）有关， 严重的泌尿系统问题尽管已有报道SUI/ISD的手术治疗效果良好， 并发症并不罕见，几乎1/3的患者需要二次手术和替代治疗 是必要的。这增加了对细胞治疗方法恢复括约肌功能的兴趣。然而，在这方面， 使用再生细胞疗法的临床研究结果仅是适度的，平均为50%。 对50%左右的患者有良好的效果。作为细胞疗法的替代方案，本研究将重点关注使用 使用我们建立的非人源性趋化因子CXCL 12（C-X-C基序趋化因子12）治疗SUI/ISD， 慢性ISD的灵长类动物（NHP）模型。使用CXCL 12的基本原理是我们发表的初步数据 报道局部注射CXCL 12，而不是细胞疗法，恢复了尿道括约肌的结构和功能， 在患有慢性ISD的NHP中。虽然这些实验为这种治疗方法提供了原理证明， 通过探索潜在的机制，拟议的实验将不会证实和大大扩展这一发现。 这些有益的效果。此外，我们将通过评估括约肌功能更好地定义长期功能 以及注射后增加的时间点的结构。拟议中的实验将检验这一假设， CXCL 12介导的细胞向尿道括约肌的移动是导致膀胱癌的主要潜在机制。 尿道括约肌结构和功能的长期再生。为了解决这个问题，我们 提出了一个深入的评估括约肌细胞和基质细胞和基质的时程变化， 在将CXCL 12局部注射到NHP的尿道括约肌中之后，将组合物持续长达12个月， 慢性ISD。目的是：1）评估局部注射CXCL 12对细胞增殖的时程效应。 和尿道括约肌的结构发育。我们将使用新的多重/多光谱分析， 尿道括约肌复合体，以检验我们的工作假设，即部分骨髓移植后， 慢-GFP转导的BMCs，CXCL 12将刺激GFP-BMCs向尿道括约肌的动员 复杂，这些细胞提供与持续神经， 血管，肌肉再生与天然组织样架构;和2）测量时间过程的影响 对括约肌功能的影响。我们将进行尿动力学测量休息和神经刺激 括约肌和膀胱压力，并量化排尿模式作为功能相关的结构 CXCL 12治疗的效果（目的1），以检验我们的假设，即CXCL 12恢复功能性肌肉， 支持神经支配的括约肌压力的神经支配;静息和神经刺激的括约肌血流;以及 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 治疗晚期绝经前慢性ISD。它还将提供有关细胞动员的新信息 CXCL 12的能力，这些动员的细胞如何促进组织再生和长期疗效 of this therapeutic治疗approach方法.

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.