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：
10649540
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/10649540
关键词：
Abdomen Atrophic Basic Science Biocompatible Materials Biological Process Birth trauma Cell Death Cell Separation 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 Population Dynamics Pregnancy Prevention Prevention strategy Prevention therapy Preventive measure Proliferating 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 Urinary Incontinence Woman cost directed differentiation epidemiology study functional disability immune cell infiltrate 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.

项目摘要产妇分娩是骨盆底肌肉功能障碍的主要危险因素和由此产生的骨盆底疾病，包括骨盆器官脱垂，尿液和粪便失禁。尽管患病率很高，但严重的病毒性和与骨盆底疾病相关的经济负担，预防策略是几乎不存在潜在的病理生理学。因此，我们的长期目标是发展新的，微创组织的发展用于预防和治疗骨盆肌肉功能障碍的工程疗法。我们对骨盆的试点研究骨盆器官脱垂和模拟的大鼠模型的darous妇女的地板肌肉形态计量学特性出生损伤表现出实质性的变性，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，并且与临床不良结局有关。我们开发了一种新型的组织特异性注射细胞外基质水凝胶，该水凝胶源自脱细胞猪骨骼肌，促进肌肉再生。该提议围绕整体假设骨骼肌基质水凝胶（包含组织特异性提示）可以单独传递出生损伤以防止骨盆底肌肉功能障碍或在出生后不良适应后的恢复后反向骨盆底肌肉功能障碍。我们将在与翻译相关的怀孕模型中检验这一假设通过比较未处理和处理的骨盆底肌肉表型，功能和转录特征出生损伤后的多个时间点，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的细胞极低侵入性再生疗法在骨盆底肌肉中的作用出生损伤后的恢复以及对涉及的生物过程的基本知识调节骨盆底肌肉再生。以上具有很高的发展潜力预防性和治疗性策略来抵消骨盆肌肉功能障碍和相关的骨盆底疾病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechanisms governing protective pregnancy-induced adaptations of the pelvic floor muscles in the rat preclinical model.

DOI：
10.1016/j.ajog.2021.11.1353
发表时间：
2022-05
期刊：
American journal of obstetrics and gynecology
影响因子：
9.8
作者：
通讯作者：

Muscle stem cells and fibro-adipogenic progenitors in female pelvic floor muscle regeneration following birth injury.

DOI：
10.1038/s41536-022-00264-1
发表时间：
2022-12-16
期刊：
NPJ Regenerative medicine
影响因子：
7.2
作者：
Sesillo FB;Rajesh V;Wong M;Duran P;Rudell JB;Rundio CP;Baynes BB;Laurent LC;Sacco A;Christman KL;Alperin M
通讯作者：
Alperin M