Regenerative therapy for stress urinary incontinence and pelvic floor disorder

压力性尿失禁和盆底疾病的再生疗法

• 批准号: 10370405
• 负责人: TOM F LUE
• 金额: $ 56.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370405
• 关键词: Acoustics; Affect; Australia; Biological; Birth trauma; CRISPR interference; Cell Differentiation process; Cell Proliferation; Cells; Combined Modality Therapy; Data; Devices; Drug or chemical Tissue Distribution; Dyspareunia; England; Exercise; Female; Functional disorder; GDF8 gene; Goals; Gynecology; In Situ; Incidence; Infection; Injury; Institutional Review Boards; Lead; Methods; Modeling; Molecular; Muscle Fibers; Muscle satellite cell; Myoblasts; Myopathy; Natural regeneration; Nerve Regeneration; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Pattern; Pelvic Floor Disorders; Pelvic Pain; Pelvic floor structure; Persons; Phase I/II Clinical Trial; Physiologic pulse; Prevalence; Prevention; Preventive; Protein-Lysine 6-Oxidase; Ptosis; Publishing; Rattus; Recovery; Research; Research Personnel; Shock; Strenuous Exercise; Stress Urinary Incontinence; Striated Muscles; Structure; Therapeutic; Tissue Differentiation; Tissues; Urethra; Urology; Vagina; Vaginal delivery procedure; Woman; base; design; experience; experimental study; human disease; improved; in vivo; innovation; mechanical stimulus; minimally invasive; muscle regeneration; novel; pelvic organ prolapse; regenerative; regenerative approach; regenerative therapy; satellite cell; stem; stem cells; technological innovation; tissue regeneration

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.

项目总结/摘要： 压力性尿失禁（SUI）和骨盆底疾病（PFD）是影响数百万妇女的主要问题 国际吧非手术疗法大多无效且不持久。最有效的是补片手术 SUI和盆腔器官脱垂（POP）。然而，许多妇女在手术后出现了严重的并发症 导致在美国禁止将所有补片用于POP（FDA 2019年4月16日）。我们开始研究再生 2002年，治疗。我们的长期目标是更好地了解病理生理学， 对患有SUI和PFD的女性进行侵入性和高效的再生治疗。 在本项目中，我们提出了一种新的机械刺激原位激活横纹肌卫星细胞 我们最近开发了微能量声脉冲（MAP）作为SUI和PFD的再生疗法。在 严重的情况下，我们提出了一个组合的肌肉生长抑制素抑制通过集群定期间隔短 回文重复序列干扰（CRISPRi）和MAP以实现更好的结果。我们的主要假设是 组织驻留祖细胞的功能障碍是SUI、PFD和肌生长抑制素抑制的主要原因 其次是MAP将提供最大限度恢复尿道和盆底结构的最佳策略， 功能 激活和分化组织驻留干/祖细胞的能力将是一种强大的治疗方法 这种能力是我们正在开发的创新的基础， 促进肌肉再生以治疗SUI和PFD。这些目标导致我们提出1）。阐明和 比较可逆性和不可逆性压力性尿失禁和骨盆底疾病的病理生理学 在阴道分娩损伤诱导的大鼠模型中; 2）.比较肌肉生长抑制素抑制的分子机制， 微能声脉冲对横纹肌卫星细胞可逆和不可逆再生的影响 SUI和PFD模型; 3）.比较肌生长抑制素抑制的治疗和预防效果， 微能声脉冲治疗大鼠压力性尿失禁及盆底损伤的实验研究 disorder.该项目的成功完成将为设计更好的预防和 为数百万患有SUI和PFD的妇女提供治疗。