Prevention of pelvic floor muscle dysfunction with extracellular matrix hydrogel

细胞外基质水凝胶预防盆底肌肉功能障碍

基本信息

批准号：
10416040
负责人：
Marianna Alperin
金额：
$ 63.76万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2020-09-30 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10416040
关键词：
Abdomen Atrophic Basic Science Biocompatible Materials Biological Process Birth trauma Cell Death Cell Therapy Cells Cesarean section Cessation of life Childbirth Chronic Clinical Collagen Cues Development Economic Burden Epidemic Exploratory/Developmental Grant for Diagnostic Cancer Imaging Extracellular Matrix Family suidae Fecal Incontinence Female Fibrosis Functional disorder Gene Expression Gene Expression Profile Goals High Prevalence Histology Hydrogels In Vitro Injectable Injections Injury Intervention Knowledge Lead Lung Measures Modeling Morbidity - disease rate Muscle Muscle function Muscle satellite cell Muscular Atrophy Natural regeneration Organ Outcome Pathologic Patients Pelvic Floor Disorders Pelvic Floor Muscle Pelvic floor dysfunction Pelvic floor structure Pelvis Phenotype Pilot Projects Population Dynamics Pregnancy Prevention Prevention strategy Prevention therapy Preventive measure Property Public Health Quality of life Rattus Recovery Regulation Rehabilitation therapy Risk Risk Factors Role Saline Signal Pathway Skeletal Muscle Testing Therapeutic Time Tissue Engineering Tissues Translational Research Tumor-infiltrating immune cells Urinary Incontinence Woman cost epidemiology study functional disability immunoregulation improved in vivo injured injury recovery innovation limb injury mechanical properties minimally invasive modifiable risk muscle degeneration muscle regeneration novel novel therapeutics parous pelvic organ prolapse preempt pregnant preservation prevent protein expression recruit regeneration potential regenerative therapy repaired reparative process response scaffold single-cell RNA sequencing soft tissue stem cells therapeutically effective

项目摘要

PROJECT SUMMARY Maternal childbirth injury is the leading risk factor for pelvic floor muscle dysfunction and the resultant pelvic floor disorders, which include pelvic organ prolapse and urinary and fecal incontinence. Despite high prevalence, significant morbidities, and economic burden associated with pelvic floor disorders, preventative strategies are almost non-existent, and the available treatments are delayed and compensatory as they do not directly target the underlying pathophysiology. Thus, our long-term goal is the development of new, minimally invasive tissue- engineered therapies for the prevention and treatment of pelvic muscle dysfunction. Our pilot studies of pelvic floor muscle morphometric properties in parous women with pelvic organ prolapse and the rat model of simulated birth injury demonstrate substantial degeneration, specifically cell death, myofiber atrophy and fibrosis. The above alterations render muscles insensitive to rehabilitation and are associated with poor clinical outcomes. We developed a novel tissue-specific injectable extracellular matrix hydrogel, derived from decellularized porcine skeletal muscles, which promotes muscle regeneration. This proposal is centered around the overall hypothesis that the skeletal muscle matrix hydrogel, which contains tissue-specific cues, can be delivered alone at the time of birth injury to prevent pelvic floor muscle dysfunction or following a maladaptive post birth injury recovery to reverse pelvic floor muscle dysfunction. We will test this hypothesis in our translationally-relevant pregnant model by comparing untreated and treated pelvic floor muscle phenotypic, functional, and transcriptional signatures at multiple time points following birth injury and determining mechanisms by which the extracellular matrix hydrogel enhances regeneration. Collectively, this innovative study will provide comprehensive and functionally relevant assessments of the role of this low-cost acellular minimally invasive regenerative therapy in pelvic floor muscle recovery following birth injury and the fundamental knowledge of the biological processes involved in the regulation of pelvic floor muscle regeneration. The above has a high potential for the development of novel preventative and therapeutic strategies to counteract pelvic muscle dysfunction and the related pelvic floor disorders.

项目概要产妇分娩损伤是盆底肌肉功能障碍及其导致的盆底肌功能障碍的主要危险因素疾病，包括盆腔器官脱垂以及尿失禁和大便失禁。尽管患病率很高，与盆底疾病相关的重大发病率和经济负担，预防策略是几乎不存在，并且可用的治疗方法是延迟的和补偿性的，因为它们不直接针对潜在的病理生理学。因此，我们的长期目标是开发新的微创组织- 用于预防和治疗盆腔肌肉功能障碍的工程疗法。我们对骨盆的试点研究经产妇盆腔器官脱垂的底肌形态特征及模拟大鼠模型产伤表现出严重的退化，特别是细胞死亡、肌纤维萎缩和纤维化。以上改变使肌肉对康复不敏感，并与不良的临床结果相关。我们开发了一种新型组织特异性可注射细胞外基质水凝胶，源自脱细胞猪骨骼肌，促进肌肉再生。该提案围绕总体假设含有组织特异性线索的骨骼肌基质水凝胶可以在当时单独输送产伤后预防盆底肌肉功能障碍或产后损伤适应不良后恢复逆转盆底肌肉功能障碍。我们将在我们的翻译相关怀孕模型中测试这个假设通过比较未经治疗和治疗的盆底肌肉表型、功能和转录特征产伤后的多个时间点并确定细胞外基质水凝胶的机制增强再生。总的来说，这项创新研究将提供全面且功能相关的评估这种低成本非细胞微创再生疗法在盆底肌肉中的作用产伤后的恢复以及涉及产伤的生物过程的基本知识盆底肌肉再生的调节。以上具有较高的小说开发潜力对抗盆腔肌肉功能障碍及相关盆底的预防和治疗策略失调。