Overactive Bladder Urothelium: The ACh loop, immune response and microbiota
膀胱过度活跃的尿路上皮:乙酰胆碱循环、免疫反应和微生物群
基本信息
- 批准号:9257256
- 负责人:
- 金额:$ 22.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-15 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAcetylcholineAddressAffectAgeBacteriaBacterial InfectionsBindingBiologicalBiopsyBladderBladder Urothelial CellBladder UrotheliumBladder mucosaBloodCell Culture TechniquesCellsCholinergic AgonistsCommunitiesDataDefense MechanismsDevelopmentDiseaseElderlyEtiologyFoundationsFrequenciesFunctional disorderGastrointestinal tract structureGoalsHumanImmune responseIncontinenceInnate Immune ResponseInterleukin ReceptorKnowledgeLower urinary tractMeasuresMediatingMembraneMicturition ReflexModelingMolecularMucous MembraneMuscarinic Acetylcholine ReceptorMuscle CellsNeurotransmittersNicotinic ReceptorsOveractive BladderOxotremorinePathway interactionsPatientsPatternPeptide ReceptorPeptidesPlayPoisonPrevalenceProductionQuality of lifeReceptor Mediated Signal TransductionReceptor SignalingSensorySentinelSignal TransductionSkinSmooth MuscleSymptomsSyndromeSystemTLR1 geneTLR2 geneTLR4 geneTLR6 geneTestingToll-like receptorsUrineUrothelial CellUrotheliumWomanWorkage relatedantimicrobialantimicrobial peptideautocrinechemokinecommensal microbescytokinedetrusor muscleinterleukin-22keratinocytemenmethacholinemicrobialmicrobiotanovelpathogenic bacteriapublic health relevancereceptorreceptor expressionreceptor-mediated signalingresponsetargeted treatmenttheoriestherapeutic targeturinary
项目摘要
DESCRIPTION (provided by applicant): Urothelium dysfunction contributes to diverse lower urinary tract disorders, e.g. overactive bladder syndrome (OAB). OAB is age-related and highly prevalent in both men and women. In OAB, increased neurotransmitter acetylcholine (ACh) release and signaling via nicotinic and muscarinic receptors (mAChR) expressed by detrusor muscle cells leads to dysregulated bladder contraction, and thus frequency, urgency and sometimes incontinence. Recent evidence shows that urothelial cells also release ACh and express mAChRs, establishing the theory that an ACh autocrine loop contributes to urothelial sensory dysfunction. Whether this autocrine loop also contributes to the urothelium's protective functions, e.g. innate immune responses mediated by Toll-like receptors (TLR) or IL22 remains unknown - TLRs detect bacterial products, while the cytokine IL22 regulates antimicrobial peptide (AMP) expression; thus, they both control bacterial infection. Since mAChR-mediated signal transduction depends on PI3 kinase activation, which also modulates the TLR-mediated innate immune response, we propose a new OAB paradigm, in which an ACh autocrine loop affects the ability of human urothelial cells (HUCs) to generate proper TLR- and IL22-mediated innate immune responses. We hypothesize that HUCs from OAB patients display two abnormalities: 1) dysfunctional TLR signaling; and 2) altered IL22- regulated AMP production. We further hypothesize that these urothelial changes in OAB are differentially modulated by bacterial products from the newly discovered urinary microbiota. For this study, we established a system to culture primary urothelial cells from human bladder biopsies. We expect that results from this study will establish: 1) increased ACh response affects innate immune responses mediated by IL22 and TLRs; 2) IL22 as an important innate component of the human urothelium that maintains protection against bacterial infection; 3) bacterial products from commensal and pathogenic bacteria differentially affect TLR- and IL22- mediated responses in urothelium of OAB versus non-OAB patients. This new knowledge will advance understanding of urothelium dysfunctions in OAB in the elderly.
描述(由申请方提供):尿路功能障碍导致多种下尿路疾病,例如膀胱过度活动综合征(OAB)。OAB与年龄有关,在男性和女性中都非常普遍。在OAB中,通过逼尿肌细胞表达的烟碱和毒蕈碱受体(mAChR)增加的神经递质乙酰胆碱(ACh)释放和信号传导导致膀胱收缩失调,从而导致频率、紧迫性和有时失禁。最近的证据表明,尿路上皮细胞也释放ACh和表达mAChR,建立了ACh自分泌回路有助于尿路上皮感觉功能障碍的理论。这种自分泌回路是否也有助于尿路上皮的保护功能,例如由Toll样受体(TLR)或IL 22介导的先天免疫反应仍然未知-TLR检测细菌产物,而细胞因子IL 22调节抗菌肽(AMP)表达;因此,它们都控制细菌感染。由于mAChR介导的信号转导依赖于PI 3激酶激活,这也调节TLR介导的先天免疫应答,我们提出了一个新的OAB范式,其中ACh自分泌环影响人尿路上皮细胞(HUCs)产生适当的TLR和IL 22介导的先天免疫应答的能力。我们假设来自OAB患者的HUCs显示两种异常:1)TLR信号传导功能障碍;和2)改变的IL 22调节的AMP产生。我们进一步假设OAB中的这些尿路上皮变化受到来自新发现的尿液微生物群的细菌产物的差异调节。在这项研究中,我们建立了一个从人膀胱活检组织中培养原代尿路上皮细胞的系统。我们期望本研究的结果将确定:1)增加的ACh应答影响由IL 22和TLR介导的先天性免疫应答; 2)IL 22作为人尿道炎的重要先天性组分,其维持对细菌感染的保护; 3)来自细菌和病原性细菌的细菌产物在OAB患者与非OAB患者的尿道炎中差异性地影响TLR和IL 22介导的应答。这一新的知识将促进对老年人OAB中泌尿系统功能障碍的理解。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('PHONG T LE', 18)}}的其他基金
Aging and thymopoiesis: Changes in stroma, T-presursors
衰老和胸腺生成:基质、T 前体的变化
- 批准号:
7475885 - 财政年份:2006
- 资助金额:
$ 22.34万 - 项目类别:
Aging and thympopoiesis: Changing in stroma, T-precursors
衰老和胸腺生成:基质、T 前体的变化
- 批准号:
7103353 - 财政年份:2006
- 资助金额:
$ 22.34万 - 项目类别:
Aging and thymopoiesis: Changes in stroma, T-presursors
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7273629 - 财政年份:2006
- 资助金额:
$ 22.34万 - 项目类别:
EPITHELIAL DIFFERENTIATION COMPARISON OF SKIN & THYMUS
皮肤上皮分化比较
- 批准号:
3156959 - 财政年份:1988
- 资助金额:
$ 22.34万 - 项目类别:
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