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）：尿失禁影响全球超过2亿患者，并与生活质量的显着降低相关。目前的治疗选择有局限性，需要选择。细胞疗法治疗女性尿道括约肌缺陷（USD）相关的压力性尿失禁继续在临床前研究和临床试验中进行测试。 这是RO 1的更新应用，其初始目标是开发稳定USD的非人灵长类动物（NHP）模型，然后测量自体骨骼肌前体细胞（skMPC）治疗对括约肌结构和功能的长期影响。 结果表明，横切阴部神经支配的女性NHP的尿道括约肌复合体产生稳定的（损伤后12个月）USD和括约肌注射skMPC产生同样稳定的结构和功能的改善。更新申请将利用USD的NHP模型来解决关于这种治疗方法的知识方面的剩余和额外差距。 1)最初的研究提供的证据表明，至少部分地，注射的细胞主动地结合到括约肌组织中，但是它们也可以调节天然细胞向括约肌的迁移。 因此，拟议的研究将更明确地探索“细胞”， 掺入与刺激细胞迁移”作为注射细胞再生括约肌组织的中心作用模式。2)细胞疗法在已建立/稳定的USD中的疗效-通常的临床表现-仍然不清楚，现在将在该模型中进行测试。 研究将比较直接括约肌与静脉注射的疗效-这可以提供更广泛的临床接受。 在用标记的自体标记的骨髓祖细胞（BMC）进行骨髓移植后，自体标记的skMPC将在括约肌去神经支配后6周或去神经支配后6个月静脉内或直接施用到括约肌复合体中。 目标1. 在USD的NHP模型中测量并比较skMPC治疗途径和skMPC治疗时间对尿道括约肌复合体结构变化的影响。 假设刺激天然细胞迁移是一个重要的过程，通过这个过程，注射的细胞有助于括约肌复合体的再生。 因此，结构 括约肌的再生在局部细胞治疗组中将更大（不管 定时），因为与全身注射相比，初始直接细胞-细胞内容物增强了趋化性旁分泌活性并增加了天然细胞（BMC）向括约肌的迁移。目的2是比较skMPC治疗对尿道括约肌功能变化（括约肌压力和血流的躯体和肾上腺素能反射控制）的途径和时机。假设功能性再生将反映对括约肌复合体的结构、血管和肌肉成分的治疗效果。预计拟议研究的结果将有助于更好地定义细胞治疗的机会窗口， 可能的有效给药途径和细胞治疗在动物模型中的作用方式，该动物模型位于临床转化的节点。