Bladder Mucosal Dysfunction During Aging
衰老过程中的膀胱粘膜功能障碍
基本信息
- 批准号:10371207
- 负责人:
- 金额:$ 59.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAgeAgingAnatomyAnimalsArchitectureAutophagocytosisBehaviorBiochemicalBioenergeticsBiogenesisBiological AssayBladderBladder ControlBladder DiseasesBladder DysfunctionBladder mucosaCalciumCathepsins BCell AgingCell CommunicationCell surfaceCellsComplexCoupledCytoplasmDataDefectDevelopmentDiagnosisDiseaseDrug TargetingElderlyEsthesiaEtiologyEventExocytosisFibrosisFoundationsFunctional disorderGenus HippocampusHealthHealth Care CostsHomeostasisHydrolaseImageImaging TechniquesImpairmentIncontinenceInstitutionalizationInterdisciplinary StudyLeadLower urinary tractLysosomesMeasurementMeasuresMediator of activation proteinMetabolic PathwayMetforminMitochondriaModalityModelingMolecularMorphologyMuscle functionNervous system structureNeurologicOrganOrganellesOxidative StressPathway interactionsPeptide HydrolasesPhenotypePhysiologyPopulationPositioning AttributeProcessProductionQuality of lifeQuantitative Reverse Transcriptase PCRRattusReactive Oxygen SpeciesResearchResourcesRoleSignal PathwaySignal TransductionSocietiesStressSumSymptomsUrinary IncontinenceUrodynamicsUrothelial CellUrotheliumWestern Blottingafferent nerveage effectage relatedagedanti agingcostdetrusor muscleimprovedin vivoinsightinterdisciplinary approachlower urinary tract symptomsmechanical stimulusmitochondrial dysfunctionprotein degradationreceptorsensory inputside effecttooltranscription factor
项目摘要
Lower urinary tract symptoms (LUTS), in particular storage symptoms (urinary incontinence) are a
major health related problem in the elderly. Yet, there remains insufficient understanding of how aging alters
normal bladder physiology, and how these changes contribute to the etiology of LUT disorders in the elderly.
Much of research past and present, has focused on detrusor muscle function and changes in the central
neurological control of aging-related LUT function; however, much less is known about the role of the
urothelium (UT) in these events. While previously thought of as a simple barrier, the urothelium communicates
with the CNS via a local urothelial-afferent signaling pathway. Our preliminary data show that aged UT has
altered mitochondrial function, including increased production of reactive oxygen species (ROS), which we
hypothesize leads to lysosomal dysfunction, altered release of mediators, and defects in UT-afferent signaling,
culminating in abnormal urodynamic behavior. Thus, our overall hypothesis is that age-related changes in the
UT and adjacent bladder wall result in a pro-aging cellular phenotype that disrupts UT-cell signaling resulting in
abnormal urodynamic behavior in the elderly.
Our multidisciplinary research team will elucidate the effect of aging and oxidative/lysosomal stress on
urothelial physiology and the impact this has on cross talk between the UT and other cells within the bladder
wall. Using an aging (3-30 mo) rat model, we will in Aim #1 define how changes in bioenergetics and oxidative
stress impact urothelial aging by using functional assays to measure changes in both mitochondrial function
and architecture. In Aim #2, we will determine how lysosomal dysfunction contributes to urothelial aging. Here
we will use stereology as well as biochemical and morphological tools to examine why degradation and
mitophagy are impaired in aging urothelium. In Aim #3, we will determine if increasing mitochondrial/lysosomal
function will enhance UT-signaling and resultant bladder function. We will use a multi-disciplinary approach
including measurement of transmitter release and sophisticated imaging techniques coupled with recording
bladder afferent nerve activity to examine how aging and increased mitochondrial oxidative stress alters UT-
cell communication. In each aim, we will also examine whether treatments (mitotempo; metformin) that reduce
oxidative stress/lysosome dysfunction can improve urothelial (and in vivo bladder function) in aged rats. In
sum, our intriguing preliminary data combined with our extensive expertise and resources places our research
team in a unique position to examine how direct and indirect factors promote UT dysfunction in bladder aging.
下尿路症状 (LUTS),特别是储存症状(尿失禁)是
老年人的主要健康相关问题。然而,人们对衰老如何改变仍缺乏足够的了解
正常膀胱生理学,以及这些变化如何导致老年人 LUT 疾病的病因学。
过去和现在的许多研究都集中在逼尿肌功能和中枢神经系统的变化上。
衰老相关 LUT 功能的神经控制;然而,人们对它的作用知之甚少。
这些事件中的尿路上皮(UT)。虽然尿路上皮以前被认为是一个简单的屏障,但它可以沟通
通过局部尿路上皮传入信号通路与中枢神经系统相互作用。我们的初步数据显示,老年UT有
改变线粒体功能,包括增加活性氧(ROS)的产生,我们
假设导致溶酶体功能障碍、介质释放改变以及 UT 传入信号传导缺陷,
最终导致尿动力学行为异常。因此,我们的总体假设是,与年龄相关的变化
UT 和邻近的膀胱壁会导致促衰老细胞表型,从而破坏 UT 细胞信号传导,从而导致
老年人尿动力学行为异常。
我们的多学科研究团队将阐明衰老和氧化/溶酶体应激对
尿路上皮生理学及其对 UT 和膀胱内其他细胞之间串扰的影响
墙。使用衰老(3-30 个月)大鼠模型,我们将在目标#1 中定义生物能学和氧化的变化
通过使用功能测定来测量线粒体功能的变化,压力影响尿路上皮衰老
和建筑。在目标#2中,我们将确定溶酶体功能障碍如何导致尿路上皮老化。这里
我们将使用体视学以及生化和形态学工具来研究为什么降解和
衰老的尿路上皮线粒体自噬受损。在目标#3中,我们将确定是否增加线粒体/溶酶体
功能将增强 UT 信号传导和由此产生的膀胱功能。我们将采用多学科方法
包括发射器释放的测量和与记录相结合的复杂成像技术
膀胱传入神经活动,以检查衰老和增加的线粒体氧化应激如何改变 UT-
细胞通讯。在每个目标中,我们还将检查是否可以减少治疗(mitotetempo;二甲双胍)
氧化应激/溶酶体功能障碍可以改善老年大鼠的尿路上皮(和体内膀胱功能)。在
总而言之,我们有趣的初步数据结合我们广泛的专业知识和资源,使我们的研究
该团队处于独特的地位,可以研究直接和间接因素如何促进膀胱老化中的 UT 功能障碍。
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)
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Gerard L Apodaca其他文献
Gerard L Apodaca的其他文献
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{{ truncateString('Gerard L Apodaca', 18)}}的其他基金
Role of AJC in umbrella cell function and dysfunction
AJC 在伞细胞功能和功能障碍中的作用
- 批准号:
10655616 - 财政年份:2021
- 资助金额:
$ 59.63万 - 项目类别:
Role of AJC in umbrella cell function and dysfunction
AJC 在伞细胞功能和功能障碍中的作用
- 批准号:
10482413 - 财政年份:2021
- 资助金额:
$ 59.63万 - 项目类别:
Role of AJC in umbrella cell function and dysfunction
AJC 在伞细胞功能和功能障碍中的作用
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10277473 - 财政年份:2021
- 资助金额:
$ 59.63万 - 项目类别:
Role of PIEZO Channels in Bladder Function and Dysfunction
PIEZO 通道在膀胱功能和功能障碍中的作用
- 批准号:
10662385 - 财政年份:2019
- 资助金额:
$ 59.63万 - 项目类别:
Role of PIEZO Channels in Bladder Function and Dysfunction
PIEZO 通道在膀胱功能和功能障碍中的作用
- 批准号:
9815767 - 财政年份:2019
- 资助金额:
$ 59.63万 - 项目类别:
Role of PIEZO Channels in Bladder Function and Dysfunction
PIEZO 通道在膀胱功能和功能障碍中的作用
- 批准号:
10417071 - 财政年份:2019
- 资助金额:
$ 59.63万 - 项目类别:
Role of PIEZO Channels in Bladder Function and Dysfunction
PIEZO 通道在膀胱功能和功能障碍中的作用
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10187555 - 财政年份:2019
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