Mediators for dynamic regulation of Star transcription in Leydig cells
Leydig 细胞中 Star 转录动态调节的介质
基本信息
- 批准号:9402971
- 负责人:
- 金额:$ 61.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-16 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdultAgeAndrogensAnimalsBiologyCell CountCell Differentiation processCell physiologyCellsCholesterolChromatinClinicalCongenital AbnormalityCyclic AMPCyclic AMP-Dependent Protein KinasesDataDiagnosisDiseaseEndocrineEndocrine DisruptorsEndocrine disruptionEnvironmentEnzymesErinaceidaeEventExcisionExposure toFatigueFetal DevelopmentFluorescent in Situ HybridizationGatekeepingGene Expression RegulationGenesGenetic TranscriptionGenitourinary systemHealthHereditary DiseaseImageIn VitroIndividualInfertilityKineticsKnowledgeLearningLifeMaintenanceMediator of activation proteinMessenger RNAMicrofluidicsMolecularNewborn InfantOutputParacrine CommunicationPathway interactionsPatternPhysiologic pulsePhysiologicalPlayPopulationPregnancyProductionProstatePubertyPublishingRNARNA SplicingRegulationReportingResolutionRoleSeriesSex Differentiation DisordersSignal TransductionSleep Apnea SyndromesSourceSteroidsStimulusSwellingSyndromeTechniquesTechnologyTestingTestisTestosteroneTimeTrans-ActivatorsTranscriptTranscriptional Regulationarmbone lossbone masscholesterol controldesignexperimental studyfetalgenetic regulatory proteinin vivoinnovationleydig interstitial cellmalemenmolecular imagingmouse modelmuscle formnovelparacrinepreventpublic health relevanceresponsesertoli cellsex development disordertestosterone replacement therapytooltrend
项目摘要
7. Project summary/Abstract
Leydig cells within the testis are the source of androgens that promote virility at both fetal and adult
stages, but Leydig cell populations are distinct at each age. As such, adult and fetal Leydig cells function
to synthesize testosterone in distinct cellular and endocrine environments. The AIMs of this proposal are
focused on regulation of Star, the known gatekeeper in controlling access of cholesterol to enzymatic
activity of the series of steroidogenic enzymes required for conversion to testosterone. Here we focus on
novel regulatory events that exert dynamic interactions with Star chromosomal loci that will explain how
fluctuating Star transcript accumulation can relate to changes in androgen synthesis. Previously, we
used high-resolution fluorescent in situ hybridization (HR-FISH) to localize and quantify a unique pattern
for primary, spliced, and mRNA species accumulation for Star compared to other steroidogenic genes
within single Leydig cells. We will use this and other innovative techniques to compare results from
studies that investigate individual adult and fetal Leydig cells in vitro, within MA10 cells and primary
cultures, and in vivo, within whole testes. Pulsatile LH stimulates primarily cAMP/PKA signals to promote
testosterone synthesis in adult Leydig cells. While we have substantial means to explain how Star
transcription is turned ON by LH/PKA, we understand little about what happens when the pulse is
removed, and even less about the interpulse interval. In AIM 1, we will test the hypothesis that the events
occurring at Star loci during this interval are just as critical to controlling testosterone output as the initial
stimulus. Meanwhile, the external stimuli that maintain androgen synthesis in fetal Leydig cells are less
clear, but evidence points to paracrine signals, with PKA activity playing a role. Another paracrine factor,
Sertoli cell-derived Desert Hedgehog (Hh) is known to initiate fetal Leydig cell differentiation, but its role
in their maintenance has not been tested. Once differentiated, fetal Leydig cells produce androgens at a
steadily increasing rate until late gestation. Therefore, in AIM 2, we will test the hypothesis that regulatory
events on Star loci facilitate a controlled increase in androgens within the fetal Leydig cell that compare
to those that occur during the interpulse interval in adult Leydig cells. Our findings have the potential to
explain fundamental biology underlying steroidogenic control and will have a profound impact on our
ability to explore mechanisms by which disturbances in testosterone synthesis, as in endocrine
disruption, cause significant clinical ramifications in males from all stages of life.
7.项目概要/摘要
睾丸内的间质细胞是促进胎儿和成年男性生殖力的雄激素的来源
阶段,但Leydig细胞群体是不同的,在每个年龄。因此,成人和胎儿间质细胞的功能
在不同的细胞和内分泌环境中合成睾酮。本提案的目标是
专注于调节星星,已知的看门人在控制胆固醇进入酶
转化为睾酮所需的一系列类固醇生成酶的活性。在这里,我们重点关注
新的调控事件,发挥动态相互作用与星星染色体位点,将解释如何
波动的星星转录物积累可能与雄激素合成的变化有关。此前我们
使用高分辨率荧光原位杂交(HR-FISH)来定位和量化一种独特的模式
与其他类固醇生成基因相比,星星的初级、剪接和mRNA种类积累
在单个Leydig细胞中。我们将使用这种方法和其他创新技术来比较
在体外研究单个成人和胎儿间质细胞的研究,在MA 10细胞和原代
培养和体内,在整个睾丸内。脉冲LH主要刺激cAMP/PKA信号,以促进
睾丸激素在成年睾丸间质细胞中的合成。虽然我们有足够的手段来解释星星
当LH/PKA打开转录时,我们对脉冲被激活时发生的事情知之甚少。
删除,更不用说脉冲间隔了。在AIM 1中,我们将检验事件
在此期间发生在星星位点的运动对控制睾酮输出的重要性与最初的运动一样。
刺激。同时,维持胎儿睾丸间质细胞雄激素合成的外界刺激较少
这一点很清楚,但证据表明旁分泌信号,PKA活性发挥了作用。另一个旁分泌因子,
支持细胞来源的沙漠刺猬(Hh)是已知的启动胎儿Leydig细胞分化,但它的作用,
在维护方面还没有经过测试。一旦分化,胎儿Leydig细胞产生雄激素,
直到妊娠晚期,速率稳步增加。因此,在AIM 2中,我们将测试监管的假设,
星星基因座上的事件促进胎儿间质细胞内雄激素的受控增加,
与成年睾丸间质细胞脉冲间期发生的变化相比较。我们的发现有可能
解释类固醇控制的基础生物学,并将对我们的
能够探索睾酮合成障碍的机制,如内分泌失调,
破坏,导致男性从生命的各个阶段的重大临床分歧。
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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COLIN ROBERT JEFCOATE其他文献
COLIN ROBERT JEFCOATE的其他文献
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{{ truncateString('COLIN ROBERT JEFCOATE', 18)}}的其他基金
Mediators for dynamic regulation of Star transcription in Leydig cells
Leydig 细胞中 Star 转录动态调节的介质
- 批准号:
10152639 - 财政年份:2017
- 资助金额:
$ 61.19万 - 项目类别:
Mediators for dynamic regulation of Star transcription in Leydig cells
Leydig 细胞中 Star 转录动态调节的介质
- 批准号:
9924272 - 财政年份:2017
- 资助金额:
$ 61.19万 - 项目类别:
Cytochrome P4501B1 and basal liver PPARa activity
细胞色素 P4501B1 和基础肝脏 PPARa 活性
- 批准号:
8429375 - 财政年份:2012
- 资助金额:
$ 61.19万 - 项目类别:
Cytochrome P4501B1 and basal liver PPARa activity
细胞色素 P4501B1 和基础肝脏 PPARa 活性
- 批准号:
8296906 - 财政年份:2012
- 资助金额:
$ 61.19万 - 项目类别:
Cytochrome P4501B1 and basal liver PPARa activity
细胞色素 P4501B1 和基础肝脏 PPARa 活性
- 批准号:
8638960 - 财政年份:2012
- 资助金额:
$ 61.19万 - 项目类别:
Cytochrome P4501B1 and basal liver PPARa activity
细胞色素 P4501B1 和基础肝脏 PPARa 活性
- 批准号:
8822861 - 财政年份:2012
- 资助金额:
$ 61.19万 - 项目类别:
StAR expression: Integration of Transcription with regulation via the mRNA 3'UTR
StAR 表达:通过 mRNA 3UTR 进行转录与调控的整合
- 批准号:
7661675 - 财政年份:2008
- 资助金额:
$ 61.19万 - 项目类别:
StAR expression: Integration of Transcription with regulation via the mRNA 3'UTR
StAR 表达:通过 mRNA 3UTR 进行转录与调控的整合
- 批准号:
8082656 - 财政年份:2008
- 资助金额:
$ 61.19万 - 项目类别:
StAR expression: Integration of Transcription with regulation via the mRNA 3'UTR
StAR 表达:通过 mRNA 3UTR 进行转录与调控的整合
- 批准号:
8305619 - 财政年份:2008
- 资助金额:
$ 61.19万 - 项目类别:
StAR expression: Integration of Transcription with regulation via the mRNA 3'UTR
StAR 表达:通过 mRNA 3UTR 进行转录与调控的整合
- 批准号:
7524611 - 财政年份:2008
- 资助金额:
$ 61.19万 - 项目类别:
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