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

基本信息

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
项目类别：
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

项目摘要

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。非手术疗法大多无效且不持久。最有效的是网状手术用于 SUI 和盆腔器官脱垂 (POP)。然而，许多女性在手术后出现了严重的并发症导致美国禁止所有网状材料用于 POP（FDA 2019 年 4 月 16 日）。我们开始了再生研究 2002 年 SUI 的治疗。我们的长期目标是更好地了解病理生理学并开发最小限度的治疗方法针对 SUI 和 PFD 女性的侵入性高效再生疗法。在当前的项目中，我们建议用新型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，我们建议通过成簇的规则间隔的短链来抑制肌生长抑制素的组合回文重复干扰（CRISPRi）和MAP以获得更好的结果。我们的主要假设是组织驻留祖细胞功能障碍是 SUI 和 PFD 以及肌肉生长抑制素抑制的主要原因其次 MAP 将提供尿道和盆底结构最大程度恢复的最佳策略功能。激活和分化组织驻留干细胞/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，这种能力是我们重点开发的创新的基础增强肌肉再生以治疗 SUI 和 PFD。这些目标促使我们提出建议 1)。阐明和比较可逆性和不可逆性压力性尿失禁和盆底疾病的病理生理学在阴道分娩损伤诱发的大鼠模型中； 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）。比较肌肉生长抑制素抑制的治疗和预防效果微能声脉冲治疗不可逆大鼠压力性尿失禁和盆底模型紊乱。该项目的成功完成将为设计更好的预防和治疗方案奠定科学基础。为数百万患有 SUI 和 PFD 的妇女提供治疗。