Estrogens stimulate prostatic collagen synthesis to drive fibrosis and LUTD
雌激素刺激前列腺胶原蛋白合成,促进纤维化和 LUTD
基本信息
- 批准号:10700924
- 负责人:
- 金额:$ 25.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-24 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:5 Alpha-Reductase InhibitorAddressAdrenergic alpha-AntagonistsAffectAnatomyBenignBenign Prostatic HypertrophyBiologicalBladderCRISPR/Cas technologyCaringCell physiologyCellsClinicClinicalClinical TreatmentCollaborationsCollagenCommunitiesContrast MediaDataDatabasesDepositionDevelopmentDiseaseDisease ProgressionEpithelial CellsEstrogen Receptor alphaEstrogen ReceptorsEstrogensEtiologyEventExtracellular MatrixFibroblastsFibrosisFoundationsFunctional disorderFunding OpportunitiesGenetic TranscriptionGoalsHealth Care CostsHealthcareHormone ReceptorHyperplasiaImageImaging TechniquesIn VitroInstructionLeadLinkLower urinary tractMagnetic Resonance ImagingMediatorMedicalMedicineMethodsModelingMolecularMolecular Mechanisms of ActionMonitorMusObstructionOutcomePathway interactionsPhysiologicalPre-Clinical ModelPreclinical TestingPreventionProstateProstaticProstatic hypertrophyProtocols documentationPublishingQuality of lifeReceptor SignalingReproducibilityResearchResearch Project GrantsResourcesSignal TransductionSmooth MuscleSmooth Muscle MyocytesSpecimenStratificationStromal CellsTechniquesTestingTissuesTranslatingTreatment EfficacyUrethraUrinary tractUrologyantifibrotic treatmentcell typeclinical translationclinically relevantclinically significantcosteffective therapyefficacy evaluationexperimental studygain of functionhuman diseasein vivolower urinary tract symptomsmenmortality riskmouse modelnew therapeutic targetnoveloutreachpatient populationpatient stratificationpermissivenessresponsespectrographtargeted treatmenttherapeutic targeturinaryweb site
项目摘要
PROJECT SUMMARY
Healthcare costs for lower urinary tract symptoms (LUTS) ascribed to benign prostatic hyperplasia (BPH) are in
the billions of dollars annually. Therapies for BPH/LUTS target smooth muscle contractility with α-blockers or
hyperplasia with 5α-reductase inhibitors. Although these therapies can be medicinal, they are not
effective/durable for all; this leaves millions of men in the US needing more effective therapies. The standard of
medical care for BPH/LUTS currently over-treats this patient population, in part due to a poor understanding of
etiology and progression. There is an apparent need to define what BPH represents in patient populations as
well as to identify the true anatomic, cellular, and molecular causes of the disease. This may elucidate the true
causes in development and progression of the disease as well as institute effective therapies. The overarching
goal of the O’Brien Center for Benign Urology Research is to identify the mechanisms that result in lower urinary
tract dysfunction and prostate-related LUTS. Previous studies have demonstrated prostatic collagen deposition
coincident with prostate stiffness, LUTS, and failed medical treatment supporting the concept that BPH/LUTS is,
in part, a fibrotic disease. However, this brings up a translational challenge because treatment of prostatic fibrosis
cannot occur until cellular and molecular pathways have been identified. As such, the goal is to identify the
anatomical, cellular, and molecular origins of prostate fibrosis in men with BPH/LUTS. Recently, estrogens,
specifically signaling through estrogen receptor (ER)α, was discovered to be necessary for the development of
prostatic fibrosis and LUTD in mice. Although, multiple stromal and epithelial cells express ERα, a subpopulation
of ERα positive prostatic fibroblasts and/or smooth muscle cells could be responsible for increased collagen
deposition. These cells are sensitive to estrogens and produce large amounts of collagen in vitro and in vivo.
Aim 1 will address the ER molecular mechanism of action in the transcription of Col1a1 by determining if classical
or non-classical ER signaling is necessary. Next, collagen accumulation has been linked with BPH/LUTS, but it
is uncertain if collagen/fibrosis acts independently or in collaboration with prostate hyperplasia; Aim 2 will test
the hypothesis that gain of collagen function promotes LUTD independent of prostate hyperplasia. Clinical
translation of our findings is a goal of the center; Aim 3 will test the hypothesis that clinically relevant antifibrotics
are effective in the treatment of prostatic fibrosis. Lastly, stratification of men with fibrotic prostates is imperative
to increase treatment efficacy. To address this challenge, advanced and novel collagen MR imaging techniques
will be used to assess whether prostatic fibrosis can be identified in preclinical models. By establishing cellular
and molecular mechanistic connections between fibrosis and BPH/LUTS as well as preclinical testing and patient
stratification our collaborative and synergistic research, Project 1 will lay the groundwork for impactful discoveries
that elucidate an important etiology of BPH/LUTS and may ultimately translate into the clinic.
项目总结
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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WILLIAM A RICKE其他文献
WILLIAM A RICKE的其他文献
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{{ truncateString('WILLIAM A RICKE', 18)}}的其他基金
Estrogen pathways in the development of prostatic fibrosis and lower urinary tract dysfunction
前列腺纤维化和下尿路功能障碍发展中的雌激素途径
- 批准号:
10378476 - 财政年份:2021
- 资助金额:
$ 25.44万 - 项目类别:
Estrogen pathways in the development of prostatic fibrosis and lower urinary tract dysfunction
前列腺纤维化和下尿路功能障碍发展中的雌激素途径
- 批准号:
10597683 - 财政年份:2021
- 资助金额:
$ 25.44万 - 项目类别:
Elucidating hallmarks of aging in the development of lower urinary tract dysfunction (LUTD)
阐明下尿路功能障碍 (LUTD) 发展中的衰老特征
- 批准号:
10346265 - 财政年份:2021
- 资助金额:
$ 25.44万 - 项目类别:
Elucidating hallmarks of aging in the development of lower urinary tract dysfunction (LUTD)
阐明下尿路功能障碍 (LUTD) 发展中的衰老特征
- 批准号:
10684318 - 财政年份:2021
- 资助金额:
$ 25.44万 - 项目类别:
Elucidating hallmarks of aging in the development of lower urinary tract dysfunction (LUTD)
阐明下尿路功能障碍 (LUTD) 发展中的衰老特征
- 批准号:
10494151 - 财政年份:2021
- 资助金额:
$ 25.44万 - 项目类别:
Cellular and molecular mediators of fibrosis in the development of urinary tract dysfunction
尿路功能障碍发展过程中纤维化的细胞和分子介质
- 批准号:
9921105 - 财政年份:2014
- 资助金额:
$ 25.44万 - 项目类别:
Estrogens stimulate prostatic collagen synthesis to drive fibrosis and LUTD
雌激素刺激前列腺胶原蛋白合成,促进纤维化和 LUTD
- 批准号:
10264805 - 财政年份:2014
- 资助金额:
$ 25.44万 - 项目类别:
Cellular and molecular mediators of fibrosis in the development of urinary tract dysfunction
尿路功能障碍发展过程中纤维化的细胞和分子介质
- 批准号:
10331481 - 财政年份:2014
- 资助金额:
$ 25.44万 - 项目类别:
Mediators of fibrosis in the development of lower urinary tract dysfunction
下尿路功能障碍发展中纤维化的介质
- 批准号:
9089461 - 财政年份:2014
- 资助金额:
$ 25.44万 - 项目类别:
Mediators of fibrosis in the development of lower urinary tract dysfunction
下尿路功能障碍发展中纤维化的介质
- 批准号:
9353662 - 财政年份:2014
- 资助金额:
$ 25.44万 - 项目类别:
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