Role of Ectonucleotidase in Voiding Function and Dysfunction
外切核苷酸酶在排尿功能和功能障碍中的作用
基本信息
- 批准号:10453611
- 负责人:
- 金额:$ 38.5万
- 依托单位:
- 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:2021-07-19 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:ATP HydrolysisAddressAdenosineAdrenergic AgentsAffectAgeAgingAgonistAppearanceAtropineAutoimmuneAutoimmune DiseasesBladderBladder ControlBladder DiseasesBladder DysfunctionBladder TissueClinicalComparative StudyCost of IllnessDataDiabetes MellitusDiseaseDrug TargetingEnzymesExhibitsFunctional disorderGenesHumanImpairmentKineticsKnock-outKnockout MiceKnowledgeLightLoxP-flanked alleleMediatingMediator of activation proteinMolecularMouse StrainsMusMuscarinic AntagonistsMuscarinicsMutationMyocardiumNatureNerveNeurodegenerative DisordersOveractive BladderPartner in relationshipPathway interactionsPatientsPersonsPharmaceutical PreparationsPhenotypePhysiologyPlayPopulationPurinoceptorReceptor SignalingRegulationRelaxationReportingResearchRodentRoleSeedsSignal PathwaySignal TransductionSmooth MuscleSmooth Muscle MyocytesStimulusSymptomsTestingTherapeuticTimeTissuesTransgenic MiceTranslatingUrinationVisceralcostdesigndiabeticdifferential expressiondisabling symptomhealth related quality of lifehuman diseasehuman femaleinsightloss of function mutationlower urinary tract symptomsmalemouse modelmutant mouse modelnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticspreventreceptorreceptor expressionreceptor functionsexsocialtelokin
项目摘要
Abstract:
Lower urinary tract symptoms (LUTS) impact a large percentage of the population with enormous financial and
social costs, and effective drugs for management of LUTS are limited. Purinergic signaling is a prominent
dysregulated pathway, which has been consistently reported in LUTS. While purinergic contractility is minimal
in normal human bladder, it increases significantly in bladders of human patients, to more closely resembles
documented rodent physiology. However, the underlying mechanism which results in these functional pathway
alterations is not known. To study this, we have identified multiple novel functional purinergic receptors and
modulators in bladder. We have demonstrated that purinergic signaling is not only important for contraction in
bladder wall, as mediated by ATP/ADP activated P2X1/P2Y12 signaling, but is also important for bladder
relaxation mediated by adenosine activated A2b receptor signaling. Furthermore, A2b receptor mediated
relaxation signaling can completely inhibit P2X1/P2Y12 mediated contractions. By comparative studies, we have
defined a key gene - ENTPD1 (also known as CD39) – that is differentially expressed in human and mouse
bladders (~ 8-fold higher in normal human bladders than in mouse). ENTPD1 is a rate-limiting enzyme
converting ATP/ADP/AMP sequentially. ENTPD1 controls the kinetics of an agonist cascade
(ATP>ADP>adenosine), and hence plays a critical role in the control of purinergic receptor expression and
function. Interestingly, human ENTPD1 mutations have been identified in autoimmune diseases and
neurodegenerative disorders, and LUTS is a prominent symptom in these diseases. Consistent with this,
impaired ATP hydrolysis has been reported in bladder tissues from LUTS patients. Therefore, we hypothesize
that ENTPD1 is a key regulator in bladder function. In support, we have preliminary data from a global Entpd1-
/- mouse, indicating that deletion of Entpd1 results in a dilated bladder with abnormal voiding phenotype. We
will test our hypothesis through the following aims: (1) We will generate a visceral smooth muscle specific
Entpd1 knockout mouse model to demonstrate the critical importance of ENTPD1 in regulating normal detrusor
contractility and bladder function; (2) We will use two ENTPD1 mutant mouse models with high and low
ENTPD1 expression levels to mimic human bladders that are normal (high) and diseased (low), and then
examine voiding function/dysfunction; (3) Through the National Disease Research Interchange (NDRI)
network, we will procure human bladder tissues, and study the expression and function of ENTPD1 in the
bladders of both sexes. We will solve the puzzles of why there are purinergic contractile differences between
human and rodent bladders, between male and female human bladders, and between normal and diseased
human bladders. We expect this study to substantially advance our understanding on how bladder contraction
and relaxation is controlled by ENTPD1 and its associated purinergic signaling. These studies have high
potential to introduce novel therapies for human LUTS patients as there are multiple targetable options.
文摘:
项目成果
期刊论文数量(0)
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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{{ truncateString('weiqun yu', 18)}}的其他基金
Role of Ectonucleotidase in Voiding Function and Dysfunction
外切核苷酸酶在排尿功能和功能障碍中的作用
- 批准号:
10292995 - 财政年份:2021
- 资助金额:
$ 38.5万 - 项目类别:
Role of Ectonucleotidase in Voiding Function and Dysfunction
外切核苷酸酶在排尿功能和功能障碍中的作用
- 批准号:
10661691 - 财政年份:2021
- 资助金额:
$ 38.5万 - 项目类别:
Role of Insulin Receptor-mediated Signaling In Underactive Bladder
胰岛素受体介导的信号传导在膀胱功能低下中的作用
- 批准号:
9805133 - 财政年份:2019
- 资助金额:
$ 38.5万 - 项目类别:
Purinergic Regulation of Bladder Interstitial Cells of Cajal
Cajal 膀胱间质细胞的嘌呤能调节
- 批准号:
9143745 - 财政年份:2015
- 资助金额:
$ 38.5万 - 项目类别:
Purinergic Regulation of Bladder Interstitial Cells of Cajal
Cajal 膀胱间质细胞的嘌呤能调节
- 批准号:
9331629 - 财政年份:2015
- 资助金额:
$ 38.5万 - 项目类别:
Purinergic Regulation of Bladder Interstitial Cells of Cajal
Cajal 膀胱间质细胞的嘌呤能调节
- 批准号:
9035629 - 财政年份:2015
- 资助金额:
$ 38.5万 - 项目类别:
Purinergic Regulation of Bladder Interstitial Cells of Cajal
Cajal 膀胱间质细胞的嘌呤能调节
- 批准号:
8707443 - 财政年份:2013
- 资助金额:
$ 38.5万 - 项目类别:
Purinergic Regulation of Bladder Interstitial Cells of Cajal
Cajal 膀胱间质细胞的嘌呤能调节
- 批准号:
8580974 - 财政年份:2013
- 资助金额:
$ 38.5万 - 项目类别:
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