Detrusor Underactivity as an HCN-mediated Failure of Resilience in Aging

逼尿肌活动不足是 HCN 介导的衰老过程中弹性丧失的原因

基本信息

批准号：
10556327
负责人：
GEORGE A KUCHEL
金额：
$ 57.6万
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：
2019-05-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10556327
关键词：
Address Adrenergic Agents Age Aging Animals Biological Bladder Bladder Diseases Brain Cells Characteristics Clinical Collaborations Cyclic AMP Cyclic Nucleotides Cytometry Data Development Disease Elderly Electrophysiology (science)Ensure Etiology Evolution Exercise Tolerance Failure Feedback Functional disorder Genomic medicine Genomics Goals Heart Rate Homeostasis Image Immunohistochemistry Impairment In Situ Incontinence Institution Investigation Ion Channel Knowledge Laboratories Mediating Mediator Methodology Modeling Molecular Mucous Membrane Mus Muscle Muscle Cells Myopathy Neurosciences Pacemakers Pathologic Perception Pharmacology Study Physiology Preventive Protein Isoforms Regulation Relaxation Reporting Research Methodology Risk Role Sensory Sensory Disorders Signal Transduction Site Sympathomimetics Symptoms System Testing Therapeutic Tissues age group cell type cyclic-nucleotide gated ion channels detrusor underactivity experimental study functional decline human old age (65+)improved innovation mind control novel novel strategies patch clamp physiologic stressor resilience response success transcriptomics urinary

项目摘要

ABSTRACT Detrusor Underactivity (DU) is a voiding impairment due to insufficient bladder muscle effort to ensure timely and efficient bladder emptying. As a disorder of volume management, DU is often associated with incontinence and other urinary symptoms, especially in later life. Despite the term suggesting a bladder muscle disorder, a key characteristic of DU is loss of sensitivity to bladder volume. Like DU, aging is also associated with loss of volume sensitivity. Moreover, aging is characterized by increasing risk of failure to adapt to biologic challenge, i.e. loss of resilience. We therefore propose that DU is not a detrusor disease, rather it is a manifestation of the nonresilient end of the spectrum of bladder sensory changes of aging. In this project we will investigate the role of a “pacemaker” ion channel in the age evolution of a control mechanism critical to bladder volume sensitivity. We hypothesize that DU is associated with the more severe age- associated changes. This knowledge will allow us to determine the control factors contributing to the loss of successful, resilient aging and the resulting non-resilience manifested as DU. To accomplish these goals will use our established mouse cystometry model to test urinary resilience and define a DU group separate from age groups. Our research methods will include single cell genomic sequencing, electrophysiology, molecular/cellular investigations, and correlative tissue-level experiments in order to address our objective. By taking advantage of the uniquely available combined expertise within the UConn Center on Aging, Neurosciences department, and on-site Jackson laboratory, we will address the goal of identifying DU pathophysiology and contributing to an improved therapeutic model which recognizes DU as an adaptive failure.

抽象的由于膀胱肌肉的努力不足以确保及时和高效的膀胱排空。作为体积管理障碍，杜通常与尿失禁和其他泌尿症状，尤其是在以后的生活中。尽管有一个术语暗示着一个膀胱肌肉障碍是DU的关键特征是对膀胱体积的敏感性丧失。像du一样，衰老也是与体积敏感性的损失有关。此外，衰老的特征是增加失败的风险适应生物学挑战，即弹性丧失。因此，我们建议DU不是逼尿病，而是相反，它是衰老的膀胱感觉变化光谱的非溶解端的表现。在这个项目我们将研究“起搏器”离子渠道在控制机制的年龄演变中的作用对膀胱体积灵敏度至关重要。我们假设DU与更严重的年龄有关关联的更改。这些知识将使我们能够确定导致丧失的控制因素成功的，有弹性的衰老和由此产生的非弹性表现为DU。实现这些目标将使用我们已建立的鼠标囊肿模型测试尿弹性并定义与DU组分开年龄组。我们的研究方法将包括单细胞基因组测序，电生理学，分子/细胞研究以及相关组织级实验，以解决我们的目标。经过利用UConn衰老中心中独特可用的组合专业知识，神经科学系和现场杰克逊实验室，我们将解决识别DU的目标病理生理学，并为改进的治疗模型做出贡献，该模型将DU视为适应性失败。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Animal modeling of lower urinary tract dysfunction associated with multiple sclerosis: Part I: Justification of the mouse model for MS research.

DOI：
10.1002/nau.24649
发表时间：
2021-04
期刊：
Neurourology and urodynamics
影响因子：
2
作者：
Ramasamy R;Smith PP
通讯作者：
Smith PP

Alzheimer's disease amyloidogenesis is linked to altered lower urinary tract physiology.

阿尔茨海默病淀粉样蛋白生成与下尿路生理学改变有关。

DOI：
10.1002/nau.24952
发表时间：
2022
期刊：
Neurourology and urodynamics
影响因子：
2
作者：
Hardy,CaraC;Ramasamy,Ramalakshmi;Rosenberg,DawnA;Kuchel,GeorgeA;Yan,Riqiang;Hu,Xiangyou;Smith,PhillipP
通讯作者：
Smith,PhillipP

Loss of resilience contributes to detrusor underactivity in advanced age.

DOI：
10.1007/s10522-022-10005-y
发表时间：
2023-04
期刊：
BIOGERONTOLOGY
影响因子：
4.5
作者：
Ramasamy, Ramalakshmi;Baker, Dylan S. S.;Lemtiri-Chlieh, Fouad;Rosenberg, Dawn A. A.;Woon, Eric;Al-Naggar, Iman M. M.;Hardy, Cara C. C.;Levine, Eric S. S.;Kuchel, George A. A.;Bartley, Jenna M. M.;Smith, Phillip P. P.
通讯作者：
Smith, Phillip P. P.

PART 2: Mouse models for multiple sclerosis research.