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: 8322335
• 负责人: James Koudy Williams
• 金额: $ 34.73万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322335
• 关键词: Address; Adult; Age; Anatomy; Autologous; Biomedical Engineering; Bladder; Canis familiaris; Cell Survival; Cell Therapy; Cell Transplantation; Cell Volumes; Cells; Characteristics; Clinical; Clinical Trials; Communities; Congenital Abnormality; Data; Deterioration; Electric Stimulation; Engraftment; Excision; Female; Gene Expression; Genetic; Genitourinary system; Health; Hormones; Human; In Vitro; Injection of therapeutic agent; Injury; Investigation; Ion Channel; Label; LacZ Genes; Location; Lower urinary tract; Macaca fascicularis; Measures; Modeling; Molecular Analysis; Motor Endplate; Muscle; Muscle Cells; Myopathy; Natural regeneration; Organ; Participant; Patients; Pattern; Pelvis; Phenotype; Physiological; Play; Primates; Property; Rattus; Reflex action; Reflex control; Reporter; Research Design; Rest; Role; Skeletal Muscle; Sphincter; Stem cells; Stimulus; Stress Urinary Incontinence; Structure; Subfamily lentivirinae; System; Therapeutic; Time; Transfection; Uncertainty; Urination; Urodynamics; Woman; Work; age group; base; electric field; follow-up; functional improvement; in vivo; middle age; muscular structure; nonhuman primate; older women; response; restoration; stressor; success; tissue regeneration; urinary

DESCRIPTION (provided by applicant): The concept of regenerating damaged tissue using selective cell transplantation has been applied clinically for a variety of muscle disorders, including stress urinary incontinence (SUI), which is a manifestation of several kinds of injuries and congenital abnormalities leading to sphincteric muscle deficiency (SMD). Results of recent clinical trials using autologous muscle-derived progenitor cells (MPCs) to treat SMD in women are promising. However, it remains unclear whether injected MPCs play a passive (bulking), or active (cell integration) role in sphincter regeneration and recent concern has been raised about the short- and long-term success rates of these clinical trials. Repeated clinical trials will take time and still lack a mechanistic explanation for their results. We propose to address these two issues in a study designed to evaluate the role of MPCs as active participants in restoration of reflex control over micturition using a cynomolgus monkey (Cyno) model of injury- induced SMD, where measures of success can be achieved in relatively few years. Two findings from our lab (one in rats and one in dogs) support the working hypothesis that injected MPCs integrate and play an active role in sphincter regeneration of females. Based on the current uncertainties associated with this therapeutic approach and the need for results that are more directly translatable to human beings, we propose to extend our studies to adult female Cyno's - at the age equivalent of 45-50 year-old women - whose genetic, anatomic, physiologic, postural, intra-pelvic bladder location, age and hormone-related changes in the genitourinary system, expose the urinary sphincter to structural and pharmacologic stressors common to middle-aged women. The specific aims are: 1. To establish a Cyno model of injury-induced SMD. This will be achieved by applying our canine model of sphincter muscle removal to adult female Cyno's and then measuring longitudinal changes in urinary sphincter structure (histological and molecular analysis of engraftment characteristics such as: sphincter content of labeled cells, injected cell viability, formation of functional motor endplates and gene expression data) and function (resting and reflex urodynamics, responses to pharmacologic and electric field stimulation) at 3mo., 6mo., 12mo., and 24 mo. post injury ( this will be equivalent to a 6 year follow-up study in human beings); and 2. To measure the effects of MPC cell therapy in the Cyno model of injury-induced SMD. First, we will optimize the culture system to produce sufficient numbers of functional lenti-LacZ transfected Cyno-derived MPCs for use in the treatment of SMD and then inject the labeled MPCs into the damaged sphincter muscle and then measure the longitudinal (same time- points as SA1) effects of these cells on sphincter function and structure. It is anticipated that the results obtained from this primate model will be directly translatable to women of this age-group, to other patients with SMD and to regeneration of other muscle tissues and muscle cell-based bioengineered organs. PUBLIC HEALTH RELEVANCE: An unanswered question about cell therapy for sphincter muscle deficiency (SMD) -associated stress urinary incontinence is whether the injected cells play a passive, or an active role in clinical improvement. The proposed studies will utilize adult female nonhuman primates to measure the longitudinal effects of muscle progenitor cells on both structural and functional changes in an injury model of SMD. We anticipate that longitudinal and parallel assessments of structure (MPC viability, functionality, and contribution to motor endplate formation) and function (resting and reflex urodynamic measures) will help determine the role (active or passive) of MPC cell therapy in restoration of a functional sphincter.

描述（由申请人提供）：使用选择性细胞移植再生受损的组织的概念已在临床上用于多种肌肉疾病，包括压力泌尿尿失禁（SUI），这表现出了几种类型的损伤和先天性异常，导致了弹态性肌肉不足（SMD）。最近使用自体肌肉衍生的祖细胞（MPC）治疗女性中SMD的临床试验的结果是有希望的。但是，尚不清楚注射的MPC是否在括约肌再生中起被动（散装）或主动（细胞整合）作用，并且对这些临床试验的短期和长期成功率提出了最近的关注。重复的临床试验将需要时间，并且仍然缺乏其结果的机械解释。我们建议在一项研究中解决这两个问题，旨在评估MPC作为损伤诱导的SMD模型恢复反射控制对排尿反射控制的作用，其中可以在相对少年的时间内实现成功的措施。我们实验室的两个发现（一只在大鼠中，一只在狗中）支持了以下假设，即注射MPC在雌性的括约肌再生中起着积极作用。 Based on the current uncertainties associated with this therapeutic approach and the need for results that are more directly translatable to human beings, we propose to extend our studies to adult female Cyno's - at the age equivalent of 45-50 year-old women - whose genetic, anatomic, physiologic, postural, intra-pelvic bladder location, age and hormone-related changes in the genitourinary system, expose the urinary sphincter to中年妇女常见的结构和药理压力源。具体目的是：1。建立损伤引起的SMD的CYNO模型。 This will be achieved by applying our canine model of sphincter muscle removal to adult female Cyno's and then measuring longitudinal changes in urinary sphincter structure (histological and molecular analysis of engraftment characteristics such as: sphincter content of labeled cells, injected cell viability, formation of functional motor endplates and gene expression data) and function (resting and reflex urodynamics, responses to pharmacologic and electric 3mo。，6mo。，12mo。和24 mo的场刺激）。受伤后（这等效于在人类中进行6年的随访研究）；和2。测量MPC细胞疗法在损伤诱导的SMD模型中的影响。首先，我们将优化培养系统，以生产足够数量的功能性Lenti-Lacz转染的CYNO衍生的MPC用于治疗SMD，然后将标记的MPC注入受损的括约肌中，然后测量纵向（与SA1的同一时间点）对这些细胞对这些细胞的影响对这些细胞对这些细胞对固定型固定功能和结构的影响。可以预料，从该灵长类动物模型获得的结果将直接转化为该年龄段的女性，其他SMD患者以及其他肌肉组织和基于肌肉细胞的生物工程器官的再生。公共卫生相关性：关于括约肌缺乏症细胞疗法（SMD）相关的压力尿失禁的一个未解决的问题是，注射细胞是被动的还是在临床改善中起源作用。拟议的研究将利用成年女性非人类灵长类动物来衡量SMD损伤模型中肌肉祖细胞对结构和功能变化的纵向作用。我们预计结构的纵向和平行评估（MPC的生存力，功能和对运动终板形成的贡献）和功能（静止和反射尿动力学测量）将有助于确定MPC细胞疗法在恢复功能型益智剂中的作用（主动或被动）。