Role of Senolytics in Lower Urinary Tract Aging and Voiding Disorders

Senolytics 在下尿路老化和排尿障碍中的作用

基本信息

批准号：
9902307
负责人：
GEORGE A KUCHEL
金额：
$ 20.5万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902307
关键词：
Address Admission activity Affect Age Aged, 80 and over Aging Anesthesia procedures Animals Attenuated Behavior Biological Biological Aging Biological Assay Bladder Bladder Control Bladder Dysfunction Bladder Tissue Brain Brain Stem Brain-Derived Neurotrophic Factor Cardiac Categories Cells Chemicals Clinical Cognition Communication Complex Control Groups DNA Damage Dasatinib Data Development Disease Drug Combinations Drug Targeting Elderly Exploratory/Developmental Grant Frequencies Functional disorder Funding Future Genomics Geroscience Goals Growth Growth Factor High Prevalence Immune Impairment Incontinence Individual Lead Link Lower urinary tract Measures Mental Depression Messenger RNA Metabolic dysfunction Micturition Reflex Modeling Mus Natural History Nature Nerve Neuregulin 1 Neuronal Plasticity Nocturia Nursing Homes Pathway interactions Patients Pattern Performance Pharmaceutical Preparations Pharmacotherapy Phenotype Physiological Population Prevention Process Publishing Quality of life Quercetin Reproducibility Risk Factors Role Science Sensory Signal Transduction Smooth Muscle Myocytes Stains Stress Symptoms Syndrome System Technology Testing Therapeutic Time Tissues Urethane Urinary Incontinence Urine age group age related aged awake beta-Galactosidase bone loss cell type density experimental study frailty functional decline lower urinary tract symptoms mouse model novel therapeutics operation palliative prevent resilience response senescence sex side effect stressor telomere translational approach treatment group urinary

项目摘要

Project Summary/Abstract Lower urinary tract symptoms (LUTS), including urinary incontinence, overactive and underactive bladder, affect over half of the elderly population and are detrimental to quality of life and independence. Current drug therapies are mostly palliative, suboptimally effective and readily abandoned by patients and prescribers due to undesirable side effects. Urinary control is a complex multi-component operation, with aging representing a major risk factor and potential biological driver of altered voiding and incontinence in older adults. Senescent cells are a cell type which accumulates in aging tissues, releasing a host of chemicals that can impair tissue function. We have found evidence of these cells in bladder tissue. Together with published studies targeting other tissues, this suggests that available drugs aimed at eliminating senescent cells could be the basis for new therapies for urinary disorders associated with aging. In this exploratory project, we will use our aging mouse model to confirm the presence of these cells and study the impact of maturation and aging on their presence in bladder tissues. We will also test the ability of senolytics, drugs that can remove these cells, to reduce senescent cell presence in bladders from old animals. Finally, we will test the ability to maintain or recover youthful bladder function in old age using senolytics using our established aging mouse cystometry model. Our findings will provide important directive and supportive data for future research into the mechanisms of senescent cell involvement with aging and associated dysfunction, and may contribute to new and more effective prevention and treatment for urinary disorders of later life.

项目摘要/摘要较低的尿路症状（LUTS），包括尿失禁，过度活跃和活动不足的膀胱，影响一半以上的老年人口，对生活质量和独立性有害。当前药物疗法大多是姑息性的，次优的有效，并且由于患者和处方者而容易抛弃不良副作用。尿控制是一个复杂的多组分操作，老化代表老年人缺血和尿失禁改变的主要危险因素和潜在的生物学驱动因素。衰老细胞是一种在衰老组织中积累的细胞类型，释放出可能损害组织的多种化学物质功能。我们在膀胱组织中发现了这些细胞的证据。与已发表的研究定位其他组织，这表明旨在消除衰老细胞的可用药物可能是与衰老相关的尿液疾病的新疗法。在这个探索性项目中，我们将使用我们的衰老小鼠模型确认这些细胞的存在并研究成熟和衰老对它们的影响存在于膀胱组织中。我们还将测试可以去除这些细胞的药物的塞溶剂剂的能力，减少来自老动物的膀胱中的衰老细胞的存在。最后，我们将测试维护或使用我们已建立的老鼠囊肿，使用鼻溶液术在老年恢复年轻的膀胱功能模型。我们的发现将为未来研究提供重要的指令和支持性数据衰老细胞参与衰老和相关功能障碍的机制，可能有助于新的以及更有效的预防和治疗以后的尿液疾病。