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：
10451696
负责人：
Marianna Alperin
金额：
$ 54.9万
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/10451696
关键词：
Acute Address Affect Animal Model Animals Atrophic Basic Science Biocompatible Materials 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 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.

项目概要横纹尿道外括约肌功能障碍是压力性尿失禁的最强预测因素，定义为在没有膀胱的情况下由于腹内压升高而导致的不自觉尿液流失收缩。大约二分之一的女性在一生中的某个阶段会受到压力性尿失禁的影响。这慢性压力性尿失禁发展背后的主要诱因已明确被确定为女性在阴道分娩过程中尿失禁机制的损伤。这令人震惊地普遍存在的病症极大地降低了生活质量，导致严重的发病率，并且给个人和社会带来巨大的经济负担。尽管如此，预防策略仍然是几乎不存在，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。上述情况很大程度上是由于我们对路径的理解导致产伤后尿道外括约肌的内在肌肉成分衰竭有限的。此外，流行的临床前研究并未利用生物学相关的怀孕动物模型产伤。为了解决现有的未满足的临床需求和知识差距，我们组建了一个跨具有多元化但互补的专业知识的学科团队，可以在两者之间的界面执行当前项目基础科学、生物材料开发和转化医学。我们将使用经过验证的生物学方法相关妊娠临床前模型可多次研究结构、分子和细胞事件产伤后横纹尿道外括约肌的恢复连续体中的点。这些基本的流程将告知新的微创组织的开发和交付的关键时间用于预防和治疗尿道肌肉功能障碍的工程治疗。具体来说，我们将测试一个新型促再生骨骼肌特异性可注射细胞外基质水凝胶，源自脱细胞猪骨骼肌，预防和逆转外尿道适应不良恢复产伤后的括约肌。总的来说，这项创新研究将提供以下方面的基础知识：参与尿道外括约肌再生调节的生物过程，以及对低成本非细胞微创的作用进行全面的功能相关评估再生疗法可对抗现有的尿失禁流行病。