Regenerative therapy for stress urinary incontinence and pelvic floor disorder

项目摘要/摘要： 压力性尿失禁(SUI)和盆底疾病(PFD)是影响数百万女性的主要问题 全世界。非手术治疗大多无效且不持久。最有效的是网状手术 用于SUI和盆腔器官脱垂(POP)。然而，许多女性在手术后遭遇了严重的并发症。 导致美国禁止使用POP的所有网眼(FDA，2019年4月16日)。我们开始研究再生能源 2002年对SUI的治疗。我们的长期目标是更好地了解病理生理学，并发展出最低限度的 对患有SUI和PFD的女性进行侵入性和高效的再生治疗。 在目前的项目中，我们提出了一种新的机械刺激来原位激活横纹肌卫星细胞。 我们最近开发了微能声脉冲(MAP)，作为SUI和PFD的再生疗法。在……里面 严重情况下，我们建议通过成簇规则间隔短的组合抑制肌肉生长抑素 回文重复干扰(CRISPRi)和MAP，以达到更好的结果。我们的主要假设是 组织驻留祖细胞功能障碍是SUI、PFD和肌肉生长抑制素抑制的主要原因 其次是MAP将为最大限度地恢复尿路和盆底结构提供最佳策略 功能。 激活和分化组织驻留的干细胞/祖细胞的能力将是一种强大的治疗方法 治疗许多人类疾病的方法，这种能力是我们为重点开发的创新的基础 促进肌肉再生治疗SUI和PFD。这些目标导致我们提出1)。为了澄清和 可逆性和不可逆性压力性尿失禁及盆底疾病的病理生理学比较 2)阴道分娩损伤大鼠模型。目的：比较肌肉生长抑素抑制作用的分子机制 微能声脉冲对可逆性和不可逆性横纹肌卫星细胞再生的影响 SUI和PFD模型；3)。比较肌肉生长抑素抑制和预防肌肉抑制素的治疗和预防效果 微能声脉冲治疗大鼠压力性尿失禁及盆底不可逆性尿失禁 无序。该项目的成功完成将为设计更好的预防和预防措施奠定科学基础 为数百万患有SUI和PFD的妇女提供治疗。

PROJECT SUMMARY/ABSTRACT: Stress urinary incontinence (SUI) and pelvic floor disorder (PFD) are major problems affecting millions of women worldwide. Non-surgical therapies are mostly ineffective and not durable. The most effective are mesh surgeries for SUI and pelvic organ prolapse (POP). However, many women suffered major complications after surgery resulting in the ban of all mesh use for POP in the USA (FDA Apr 16, 2019). We began research in regenerative therapy for SUI in 2002. Our long-term goal is to better understand the pathophysiology and develop a minimally invasive and highly effective regenerative therapy for women with SUI and PFD. In current project, we proposed to activate striated muscle satellite cells in situ with a novel mechanical stimulus we recently developed, Microenergy acoustic pulses (MAP), as a regenerative therapy for SUI and PFD. In severe cases, we propose a combination of myostatin inhibition by clustered regularly interspaced short palindromic repeats interference (CRISPRi) and MAP to achieve better results. Our main hypothesis is that dysfunction of tissue resident progenitor cells is the major contributor to SUI and PFD and myostatin inhibition followed by MAP will provide the best strategy for maximal recovery of urethra and pelvic floor structure and function. The ability to activate and differentiate tissue resident stem/progenitor cells would be a powerful curative approach for many human diseases, and this ability is the basis of the innovations we are developing for focally enhancing muscle regeneration to treat SUI and PFD. These objectives lead us to propose 1). to elucidate and compare the pathophysiology of reversible and irreversible stress urinary incontinence and pelvic floor disorders in vaginal birth injury-induced rat models; 2). to compare the molecular mechanisms of myostatin inhibition and microenergy acoustic pulses on the regeneration of striated muscle satellite cells from reversible and irreversible models of SUI and PFD; 3). to compare the therapeutic and preventive effects of myostatin inhibition and microenergy acoustic pulse therapy in the irreversible rat model of stress urinary incontinence and pelvic floor disorder. Successful completion of the project will form the scientific basis for designing better prevention and treatment for millions of women suffering from SUI and PFD.