Regeneration of the Lower Urinary Tract in Nonhuman Primates

非人类灵长类动物下尿路的再生

• 批准号: 8593424
• 负责人: James Koudy Williams
• 金额: $ 57.74万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8593424
• 关键词: Address; Adrenergic Agents; Affect; Animal Model; Apoptosis; Autologous; Blood Vessels; Blood flow; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cardiovascular system; Cell Therapy; Cells; Cellular Stress; Chemotaxis; Clinical; Clinical Trials; Collagen; Complex; Denervation; Female; Gap Junctions; Goals; Injection of therapeutic agent; Injury; Knowledge; Label; Long-Term Effects; Lower urinary tract; Measures; Modeling; Molecular Profiling; Muscle; Natural regeneration; Nerve; Nerve Fibers; Pathology; Pathway interactions; Patients; Peripheral; Play; Pre-Clinical Model; Process; Production; Quality of life; Reflex control; Rest; Role; Route; Skeletal Muscle; Smooth Muscle; Sphincter; Staging; Stem cells; Stress Urinary Incontinence; Structure; Symptoms; Technology; Testing; Therapeutic; Time; Tissues; Translations; Urethra; Urinary Incontinence; Woman; adrenergic; base; cell motility; chemokine; clinical application; comparative efficacy; efficacy testing; functional improvement; interest; intravenous injection; migration; nerve supply; nonhuman primate; paracrine; preclinical study; precursor cell; pressure; public health relevance; spinal reflex; success; treatment effect; urinary

DESCRIPTION (provided by applicant): Urinary incontinence affects more than 200 million patients worldwide, and is associated with significant reduction in quality of life Current treatment options have limitations and options are needed. Cell therapy for urinary sphincter deficiency (USD) - associated stress incontinence in women continues to be tested in preclinical studies and in clinical trials. This is a renewal application fo an RO1 whose initial goals were to develop a nonhuman primate (NHP) model of stable USD and then measure the long-term effects of autologous skeletal muscle precursor cell (skMPC) therapy on sphincter structure and function. Results indicate that transectin the pudendal innervation to the urinary sphincter complex of female NHPs produced stable (up to 12 months after injury) USD and that sphincteric injection of skMPCs produced equally stable structural and functional improvement. The renewal application will utilize the NHP model of USD to address remaining and additional gaps in knowledge concerning this therapeutic approach. 1) Initial studies provide evidence that, at least in part, injected cels actively incorporate into the sphincter tissue~ but that they may also modulate native cell migration to the sphincter. Thus, proposed studies will more definitively explore "cell incorporation vs. stimulation of cell migration" as central modes of action by which injected cells regenerate sphincter tissue. 2) The efficacy of cell therapy in established/stabl USD - the usual clinical picture - remains unclear and will now be tested in this model. ) Studies will compare the efficacy of direct sphincter vs. intravenous injection - which could afford wider clinical acceptance. Following bone marrow transplantation with labeled autologous labeled bone marrow progenitor cells (BMCs), autologous labeled skMPCs will be administered either 6 weeks post-sphincter denervation, or 6 months post-denervation, either intravenously, or directly into the sphincter complex. Aim 1. To measure and compare the route of skMPC treatment and the timing of skMPC treatment on structural changes of the urinary sphincter complex in the NHP model of USD. The hypothesis is that stimulation of native cell migration is an important process by whih injected cells contribute to regeneration of the sphincter complex. As such, structural regeneration of the sphincter will be greater in the local cell therapy groups (regardless of timing) because initial direct cell-cell content enhances chemotactic paracrine activity and increases migration of native cells (BMCs) to the sphincter compared to systemic injection. Aim 2 is to compare the route and timing of skMPC treatment on functional changes in the urinary sphincter (somatic and adrenergic reflex control of sphincter pressure and blood flow). The hypothesis is that functional regeneration will reflect treatment effects on te structural, vascular and muscular components of sphincter complex. It is anticipated that results of proposed studies will help better define the cell treatment window of opportunity, possible effective routes of administration and mode of action of cell therapy in an anial model that sits at the nexus of clinical translation.

描述（由申请人提供）：尿失禁影响了全球超过2亿患者，并且与生活质量的显着降低有关，当前治疗方案需要局限性和选择。尿括约肌缺乏症（USD）的细胞疗法 - 在临床前研究和临床试验中，女性的相关胁迫尿失禁仍在继续测试。 这是RO1的续订应用，其最初的目标是开发稳定USD的非人类灵长类动物（NHP）模型，然后测量自体骨骼肌前体细胞（SKMPC）治疗对改变改变改变改变改变改变机关的结构和功能的长期影响。 结果表明，对雌性NHP的尿括约肌的根源神经支配产生了稳定（受伤后长达12个月），并且SKMPC的括约肌注入产生了同样稳定的结构和功能改善。续订应用程序将利用USD的NHP模型来解决有关这种治疗方法的剩余和其他差距。 1）初步研究提供了证据，表明至少部分地注入了固定在括约肌组织中〜，但它们也可能调节天然细胞迁移到括约肌。 因此，提出的研究将更明确地探索“细胞” 结合与刺激细胞迁移的“作为中心的作用模式，注射细胞再生括约肌组织。2）细胞治疗在已建立/稳定的USD中的疗效 - 通常的临床情况 - 现在仍未清楚，现在将在此模型中进行测试。标记为自体骨髓祖细胞（BMC），自体skMPC将在晶格后6周或避免后6个月（静脉内）进行施用，或者直接在SKMPC的途径中进行静态的途径。 USD的NHP模型是，刺激天然细胞迁移是注射细胞的重要过程，这有助于括约肌复合物的再生。 因此，结构 在局部细胞疗法组中，括约肌的再生将更大（无论如何 时间）由于与全身注射相比，初始直接细胞含量增强了趋化性旁分泌活性，并增加天然细胞（BMC）向括约肌的迁移。 AIM 2是比较SKMPC治疗的路线和时间与尿括约肌的功能变化（体细胞和肾上腺素能反射对括约肌压力和血流）。假设是功能再生将反映对括约肌复合物的TE结构，血管和肌肉成分的治疗作用。预计拟议的研究结果将有助于更好地定义机会的细胞治疗窗口， 在临床翻译联系的肛门模型中，可能有效的给药途径和细胞疗法的作用方式。