Pathways underlying recovery of injured urethral sphincter and a novel regenerative biomaterial intervention

损伤尿道括约肌恢复的途径和新型再生生物材料干预

基本信息

批准号：
10186348
负责人：
Marianna Alperin
金额：
$ 55.78万
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：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10186348
关键词：
Acute Address Affect Animal Model Animals Atrophic Basic Science Biocompatible Materials Biological Biological Process Birth Birth trauma Bladder Bladder Control Cell Therapy Cells Chronic stress Clinical Connective Tissue Crush Injury Cues Data Deterioration Development Economic Burden Epidemic Event Extracellular Matrix Failure Family suidae Fatty acid glycerol esters Fibrosis Functional disorder Goals Human Hydrogels Hypoxia Immune Individual Inflammation Injectable Injury Intervention Investigation Knowledge Lead Life Limb structure Measures Mechanics Mediating Modeling Molecular Morbidity - disease rate Muscle Muscle satellite cell Natural regeneration Nervous System Trauma Outcome Pathogenesis Pathology Pathway interactions Pelvis Physiological Pre-Clinical Model Prevention strategy Prevention therapy Preventive Preventive measure Process Publishing Quality of life Rattus Recovery Recovery of Function Regulation Role Saline Sarcomeres Side Skeletal Muscle Skeletal muscle injury Societies Stress Urinary Incontinence Structure Symptoms Testing Therapeutic Time Tissue Engineering Tissues Translational Research Trauma Tumor-infiltrating immune cells Urethra Urethral sphincter Urinary Incontinence Urine Vaginal delivery procedure Woman Women&apos s Health Work base biomaterial development clinically relevant cost functional disability improved in vivo evaluation injury recovery innovation minimally invasive muscle regeneration nerve supply neuromuscular novel novel therapeutics preclinical study preempt pregnant pressure prevent regeneration potential regenerative regenerative therapy response stem cells therapeutically effective translational medicine

项目摘要

PROJECT SUMMARY Dysfunction of the striated external urethral sphincter is the strongest predictor of stress urinary incontinence, defined as involuntary loss of urine due to increased intraabdominal pressure in the absence of bladder contraction. Stress urinary incontinence affects approximately 1 in 2 women at some point in their lives. The primary inciting event behind the development of chronic stress urinary incontinence has been unequivocally identified as injury to the urinary continence mechanism sustained by women during vaginal deliveries. This astoundingly prevalent condition dramatically decreases quality of life, causes significant morbidity, and is associated with large economic burden to the individuals and society. Despite this, preventative strategies are almost non-existent, and the available treatments are delayed and compensatory as they do not directly target the underlying pathophysiology. The above is largely due to the fact that our understanding of the pathways that lead to failure of the intrinsic muscular components of the external urethral sphincter following birth injury remains limited. Furthermore, the prevailing preclinical studies do not utilize biologically relevant pregnant animal model of birth injury. To address the existing unmet clinical need and knowledge gaps, we assembled a cross- disciplinary team with diverse but complimentary expertise to execute the current project at the interface between basic science, biomaterial development, and translational medicine. We will use a validated and biologically relevant pregnant pre-clinical model to investigate structural, molecular, and cellular events at multiple time points across a recovery continuum of the striated external urethral sphincter following birth injury. These basic processes will inform the development of and the critical time to deliver new, minimally invasive tissue- engineered therapy for the prevention and treatment of urethral muscle dysfunction. Specifically, we will test a novel pro-regenerative skeletal muscle-specific injectable extracellular matrix hydrogel, derived from decellularized porcine skeletal muscles, in preventing and reversing maladaptive recovery of the external urethral sphincter following birth injury. Collectively, this innovative study will provide fundamental knowledge of the biological processes involved in the regulation of external urethral sphincter muscle regeneration, and comprehensive functionally relevant assessments of the role of low-cost acellular minimally invasive regenerative therapy to counteract the existing epidemic of urinary incontinence.

项目摘要条纹外部尿道括约肌的功能障碍是压力尿失禁的最强预测指标，定义为由于没有膀胱的腹腔内压力而导致尿液的非自愿丧失收缩。在生活中的某个时刻，压力尿失禁会影响大约2分之一的女性。这慢性应激尿失禁的发展背后的主要煽动事件已无疑是被确定为在阴道分娩过程中妇女维持的泌尿连续性机制的伤害。这惊人的普遍状况极大地降低了生活质量，引起明显的发病率，并且是与个人和社会的巨大经济负担有关。尽管如此，预防策略是几乎不存在潜在的病理生理学。以上是由于我们对道路的理解导致出生后外部尿道括约肌的内在肌肉成分失败有限的。此外，流行的临床前研究不利用与生物学相关的孕妇模型出生受伤。为了满足现有的未满足临床需求和知识差距，我们组装了一个交叉具有多样化但免费专业知识的纪律团队，以执行当前项目基础科学，生物材料发展和转化医学。我们将使用经过验证和生物学的相关的怀孕前临床前模型多次研究结构，分子和细胞事件出生损伤后，横纹外部尿道括约肌的恢复连续体的恢复连续。这些基本过程将为提供新的，微创组织的发展和关键时间提供信息用于预防和治疗尿道肌肉功能障碍的工程疗法。具体来说，我们将测试新型的促再生骨骼肌特异性注射细胞外基质水凝胶，源自源自脱细胞猪骨骼肌，预防和逆转适应不良的尿道恢复出生后括约肌。总的来说，这项创新的研究将提供有关调节外部尿道括约肌再生的生物过程，综合功能相关的评估低成本微创的作用再生疗法以抵消现有的尿失禁流行。