Determinants of GPCR Ciliary Localization and Effects on Signaling
GPCR 纤毛定位的决定因素及其对信号传导的影响
基本信息
- 批准号:8291058
- 负责人:
- 金额:$ 27.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-07-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAmino AcidsBardet-Biedl SyndromeBiologyBlindnessBrainCalcium ChannelCell membraneCell physiologyCellsCiliaCognitive deficitsComplexCongenital neurologic anomaliesConsensusCyclic AMPCystic Kidney DiseasesDefectDevelopmentDiseaseFailureFunctional disorderG-Protein-Coupled ReceptorsGenetic ModelsGoalsHumanHuman bodyHyperphagiaHypogonadismIn VitroKidney DiseasesKnockout MiceLaboratoriesLeadLimb structureLiver diseasesLocationMammalian CellMediatingMembraneMental RetardationMetabolismMusMutationNeuronsObesityOrganellesPathogenesisPhenotypeProcessProteinsRegulationResearchResourcesRetinal DegenerationRoleSensorySignal PathwaySignal TransductionSignaling MoleculeSignaling ProteinSorting - Cell MovementSystemTestingTimeappendagebasedevelopmental diseasefeedinginsightmelanin-concentrating hormone receptornovelprotein transportreceptorserotonin 6 receptorsomatostatin receptor 3tooltraffickingvoltage
项目摘要
Primary cilia are solitary appendages that are present on nearly all mammalian cells. Although primary cilia
were once considered vestigial, they are now recognized as important cellular sensory and signaling
organelles. Defects in the formation or function of primary cilia have been implicated in the pathogenesis of
many human developmental disorders and diseases. Yet, the functions of cilia on most cells are unknown.
Studies of cilia dysfunction and disease have revealed that the functions of primary cilia are defined by the
specific signaling proteins that localize to the membrane of the cilium. These studies have also shown that
failure of ciliary signaling proteins to properly localize can lead to disease. However, few ciliary signaling
proteins have been identified and the mechanisms that regulate their localization to cilia remain unknown. We
have discovered that the genetic defects associated with the human ciliary disorder Bardet-Biedl syndrome
(BBS) appear to affect cilia function through a mechanism that disrupts trafficking of G protein-coupled
receptors (GPCRs) onto the cilium. Importantly, this finding may represent the fundamental mechanism
underlying the pathophysiology of the seemingly diverse BBS phenotypes, including obesity, cognitive deficits,
renal cystic disease, and retinal degeneration. The central hypotheses of this proposal are; 1) Ciliary GPCRs
contain unique sequences that mediate their localization to cilia, 2) Ciliary localization of GPCRs requires
interactions with the BBS proteins, and 3) Mislocalization of ciliary receptors in BBS alters signaling and leads
to disease The objectives of this application are to define the intramolecular determinants of GPCR ciliary
localization and use this information to identify novel ciliary signaling pathways, define the intermolecular
determinants of GPCR ciliary localization and the mechanism(s) by which BBS proteins regulate this process,
and determine the effects of ciliary GPCR mislocalization on signaling. These studies will lend valuable insight
into the trafficking of ciliary GPCRs and will be used to predict novel ciliary GPCRs. Understanding the
determinants and mechanisms of ciliary localization and the effects of a lack of ciliary localization on signaling
is essential to elucidating the functions of these organelles and determining their roles in development and
disease. Although it is known that almost every cell in the human body possesses an important sensory and signaling
appendage called a primary cilium, the functions of cilia on most cells are unknown. The importance of these
organelles is highlighted by the fact that defects in primary cilia have been associated with developmental
disorders and diseases, including; obesity, renal disease, blindness, nervous system abnormalities, mental
retardation, liver disease, and limb defects. The results obtained from the proposed studies will provide
important insights into the mechanisms that control the localization of specific signaling proteins to cilia and
how disruptions in these mechanisms affect signaling.
初级纤毛是几乎所有哺乳动物细胞上都存在的单独的附属物。虽然初级纤毛
曾经被认为是退化的,现在被认为是重要的细胞感觉和信号传导
细胞器初级纤毛的形成或功能缺陷涉及到
许多人类发育障碍和疾病。然而,纤毛在大多数细胞上的功能尚不清楚。
纤毛功能障碍和疾病的研究已经揭示了初级纤毛的功能是由
定位于纤毛膜的特异性信号蛋白。这些研究还表明,
睫状体信号蛋白不能正确定位可导致疾病。然而,很少有纤毛信号
已经鉴定了蛋白质,但调节它们在纤毛上定位的机制仍然未知。我们
发现与人类睫状体疾病Bardet-Biedl综合征相关的遗传缺陷
(BBS)似乎通过破坏G蛋白偶联的运输机制影响纤毛功能。
受体(GPCRs)。重要的是,这一发现可能代表了
在看似多样的BBS表型的病理生理学基础上,包括肥胖,认知缺陷,
肾囊肿和视网膜变性。该提案的中心假设是:1)睫状体GPCR
含有介导其定位于纤毛的独特序列,2)GPCR的纤毛定位需要
与BBS蛋白质的相互作用,以及3)BBS中纤毛受体的错误定位改变了信号传导和引导
本申请的目的是定义GPCR纤毛的分子内决定簇,
定位和使用这些信息来识别新的纤毛信号通路,定义分子间
GPCR纤毛定位的决定因素和BBS蛋白调节该过程的机制,
并确定纤毛GPCR错误定位对信号传导的影响。这些研究将提供有价值的见解
的睫状GPCR的运输,并将用于预测新的睫状GPCR。了解
纤毛定位的决定因素和机制以及缺乏纤毛定位对信号传导的影响
对于阐明这些细胞器的功能和确定它们在发育中的作用至关重要,
疾病虽然我们知道人体内几乎每个细胞都有一个重要的感觉和信号传导系统,
纤毛是一种被称为初级纤毛的附属物,但大多数细胞上纤毛的功能尚不清楚。这些的重要性
初级纤毛的缺陷与发育有关,
失调和疾病,包括:肥胖、肾病、失明、神经系统异常、精神
发育迟缓、肝脏疾病和肢体缺陷。从拟议的研究中获得的结果将提供
重要的洞察机制,控制特定的信号蛋白的本地化纤毛和
这些机制的中断如何影响信号传导。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cilioplasm is a cellular compartment for calcium signaling in response to mechanical and chemical stimuli.
- DOI:10.1007/s00018-013-1483-1
- 发表时间:2014-06
- 期刊:
- 影响因子:8
- 作者:Jin, Xingjian;Mohieldin, Ashraf M.;Muntean, Brian S.;Green, Jill A.;Shah, Jagesh V.;Mykytyn, Kirk;Nauli, Surya M.
- 通讯作者:Nauli, Surya M.
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KIRK A MYKYTYN其他文献
KIRK A MYKYTYN的其他文献
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{{ truncateString('KIRK A MYKYTYN', 18)}}的其他基金
Proteomic and Transcriptional Analysis of Cilia-Dependent Dopamine Receptor 1 Signaling
纤毛依赖性多巴胺受体 1 信号传导的蛋白质组学和转录分析
- 批准号:
10017361 - 财政年份:2019
- 资助金额:
$ 27.91万 - 项目类别:
Neuronal primary cilia in dopamine receptor 1 signaling
多巴胺受体 1 信号传导中的神经元初级纤毛
- 批准号:
8970202 - 财政年份:2015
- 资助金额:
$ 27.91万 - 项目类别:
Determinants of GPCR Ciliary Localization and Effects on Signaling
GPCR 纤毛定位的决定因素及其对信号传导的影响
- 批准号:
7527276 - 财政年份:2008
- 资助金额:
$ 27.91万 - 项目类别:
Determinants of GPCR Ciliary Localization and Effects on Signaling
GPCR 纤毛定位的决定因素及其对信号传导的影响
- 批准号:
7883343 - 财政年份:2008
- 资助金额:
$ 27.91万 - 项目类别:
Determinants of GPCR Ciliary Localization and Effects on Signaling
GPCR 纤毛定位的决定因素及其对信号传导的影响
- 批准号:
7646131 - 财政年份:2008
- 资助金额:
$ 27.91万 - 项目类别:
Determinants of GPCR Ciliary Localization and Effects on Signaling
GPCR 纤毛定位的决定因素及其对信号传导的影响
- 批准号:
8109301 - 财政年份:2008
- 资助金额:
$ 27.91万 - 项目类别:
Determinants of GPCR Ciliary Localization and Effects on Signaling
GPCR 纤毛定位的决定因素及其对信号传导的影响
- 批准号:
8317818 - 财政年份:2008
- 资助金额:
$ 27.91万 - 项目类别:
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