Role of poldip2 in vascular mitochondrial dynamics
poldip2 在血管线粒体动力学中的作用
基本信息
- 批准号:9271230
- 负责人:
- 金额:$ 31.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-13 至
- 项目状态:未结题
- 来源:
- 关键词:ActinsAddressAffectAnimalsApolipoprotein EAtherosclerosisAutophagocytosisBioenergeticsBlood VesselsCardiovascular PathologyCell CycleCell Cycle ArrestCell Cycle ProgressionCell Cycle RegulationCell EnergeticsCell ProliferationCell divisionCell physiologyCellsCollaborationsCoupledCytoskeletonDataDiseaseDown-RegulationEmbryoEnsureExcisionFibroblastsGenesGlutamic AcidHigh Fat DietImpairmentInflammationInterventionKnockout MiceLeadLigationMalignant NeoplasmsMammalian CellMediatingMembrane PotentialsMetabolicMetabolic stressMetabolismMicrotubulesMitochondriaMitosisModelingMorphologyMovementMusMuscle CellsMutationNADPH OxidaseOrganellesOxidative PhosphorylationPathogenesisPathologyPathway interactionsPhasePhenotypePlayPolymeraseProcessProductionProteinsQuality ControlReactive Oxygen SpeciesRegulationResearchRoleS PhaseShapesSmooth MuscleSuggestionTestingTimeVascular DiseasesVascular Smooth Musclecell growthcell motilitydaughter celldesignhuman diseasein vivoinsightlink proteinnoveloxidative DNA damageoxidative damageprogramsprotein expressionrepairedtraffickingvascular abnormalityvascular smooth muscle cell proliferation
项目摘要
PROJECT SUMMARY
Mitochondria are dynamic organelles that continually move and re-shape through mitochondrial fusion and
fission, two highly regulated processes that control mitochondrial morphology and ensure mitochondrial
function, integrity and oxidative damage repair. Recently, the identity of some of the proteins involved in
mitochondrial dynamics in mammalian cells has started to unveil. Mutations in genes encoding for some of
these proteins have been shown to be responsible for several human diseases and cellular functions. In fact,
mitochondrial dynamics and cell cycle are coupled, and the rate of fusion and fission is regulated during the
different phases of the cell cycle, permitting appropriate phase progression and distribution of mitochondria in
daughter cells during mitosis. Our group recently identified the polymerase delta interacting protein 2 (Poldip2)
as a novel positive regulator of Nox4, and our new preliminary data suggest that Poldip2 controls the
expression of the Mitochondria-Localized Glutamic Acid-Rich Protein (MGARP), a protein responsible for
mitochondrial movement along the microtubules. These data raise the interesting possibility that Poldip2
participates in the regulation of mitochondrial movement and dynamics, and therefore cell bioenergetics. In this
proposal, we will test the hypothesis that Poldip2 controls mitochondrial fission through the regulation of
MGARP expression, which subsequently impacts cell cycle progression and proliferation. To address this
problem, we will first determine the mechanism by which Poldip2 regulates mitochondrial dynamics. In the
second aim, we will establish the functional consequences of Poldip2-mediated regulation of mitochondrial
dynamics, focusing on mitochondrial damage repair and oxidative phosphorylation (OXPHOS) capacity and
their impact in cell cycle progression. Because VSMC proliferation is known to be a critical component of
atherosclerosis, our last aim will be devoted to investigating the role of the Poldip2/MGARP pathway in a
model of partial ligation-induced atherosclerosis using inducible smooth muscle specific Poldip2 knockout mice
on an ApoE-/- background. This research program will advance our understanding of the interface between
mitochondrial dynamics and cell cycle progression, and will provide important insight into the role of two novel
proteins in vascular pathology that may represent new targets for intervention.
项目摘要
线粒体是动态的细胞器,通过线粒体融合不断移动和重塑,
分裂,两个高度调节的过程,控制线粒体形态,并确保线粒体
功能、完整性和氧化损伤修复。最近,一些蛋白质的身份参与
哺乳动物细胞中的线粒体动力学已经开始揭开面纱。基因突变编码的一些
这些蛋白质已被证明与几种人类疾病和细胞功能有关。事实上,
线粒体动力学和细胞周期是耦合的,融合和分裂的速率在细胞周期中受到调节。
细胞周期的不同阶段,允许适当的阶段进展和线粒体的分布,
有丝分裂时的子细胞。我们的团队最近发现了聚合酶δ相互作用蛋白2(Poldip 2)。
作为Nox 4的一种新的正调节因子,我们的新的初步数据表明Poldip 2控制着Nox 4的表达。
线粒体定位的富含谷氨酸的蛋白质(MGARP)的表达,该蛋白质负责
线粒体沿着微管运动。这些数据提出了一种有趣的可能性,
参与线粒体运动和动力学的调节,因此参与细胞生物能量学的调节。在这
我们将检验Poldip 2通过调节线粒体分裂来控制线粒体分裂的假设。
MGARP表达,其随后影响细胞周期进展和增殖。为了解决这个
为了解决这个问题,我们将首先确定Poldip 2调节线粒体动力学的机制。在
第二个目标,我们将建立Poldip 2介导的线粒体调控的功能后果,
动力学,重点是线粒体损伤修复和氧化磷酸化(OXPHOS)能力,
它们对细胞周期进程的影响。因为已知VSMC增殖是血管平滑肌细胞增殖的关键组成部分,
动脉粥样硬化,我们的最后一个目标将致力于研究Poldip 2/MGARP通路在动脉粥样硬化中的作用。
使用可诱导平滑肌特异性Poldip 2敲除小鼠建立部分结扎诱导的动脉粥样硬化模型
ApoE-/-基因背景这项研究计划将促进我们对
线粒体动力学和细胞周期进程,并将提供重要的洞察两个新的作用,
血管病理学中的蛋白质,可能代表新的干预目标。
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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Alejandra San Martin其他文献
Alejandra San Martin的其他文献
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{{ truncateString('Alejandra San Martin', 18)}}的其他基金
Mechanically Stressed VSMC: A Role for Slingshot Phosphatase in Inflammation
机械应力 VSMC:弹弓磷酸酶在炎症中的作用
- 批准号:
8791129 - 财政年份:2013
- 资助金额:
$ 31.41万 - 项目类别:
Mechanically Stressed VSMC: A Role for Slingshot Phosphatase in Inflammation
机械应力 VSMC:弹弓磷酸酶在炎症中的作用
- 批准号:
8620711 - 财政年份:2013
- 资助金额:
$ 31.41万 - 项目类别:
Mechanically Stressed VSMC: A Role for Slingshot Phosphatase in Inflammation
机械应力 VSMC:弹弓磷酸酶在炎症中的作用
- 批准号:
8996699 - 财政年份:2013
- 资助金额:
$ 31.41万 - 项目类别:
Mechanically Stressed VSMC: A Role for Slingshot Phosphatase in Inflammation
机械应力 VSMC:弹弓磷酸酶在炎症中的作用
- 批准号:
8439701 - 财政年份:2013
- 资助金额:
$ 31.41万 - 项目类别:
Mechanically Stressed VSMC: A Role for Slingshot Phosphatase in Inflammation
机械应力 VSMC:弹弓磷酸酶在炎症中的作用
- 批准号:
9206517 - 财政年份:2013
- 资助金额:
$ 31.41万 - 项目类别:
Mechanism of SSH1L Phosphatase Activation in VSMC: Role in Vascular Pathology
VSMC 中 SSH1L 磷酸酶激活的机制:在血管病理学中的作用
- 批准号:
7925118 - 财政年份:2009
- 资助金额:
$ 31.41万 - 项目类别:
Role of poldip2 in vascular mitochondrial dynamics
poldip2 在血管线粒体动力学中的作用
- 批准号:
9100845 - 财政年份:2009
- 资助金额:
$ 31.41万 - 项目类别:
Mechanism of SSH1L Phosphatase Activation in VSMC: Role in Vascular Pathology
VSMC 中 SSH1L 磷酸酶激活的机制:在血管病理学中的作用
- 批准号:
8119389 - 财政年份:2009
- 资助金额:
$ 31.41万 - 项目类别:
Mechanism of SSH1L Phosphatase Activation in VSMC: Role in Vascular Pathology
VSMC 中 SSH1L 磷酸酶激活的机制:在血管病理学中的作用
- 批准号:
7928075 - 财政年份:2009
- 资助金额:
$ 31.41万 - 项目类别:
Mechanism of SSH1L Phosphatase Activation in VSMC: Role in Vascular Pathology
VSMC 中 SSH1L 磷酸酶激活的机制:在血管病理学中的作用
- 批准号:
7510750 - 财政年份:2008
- 资助金额:
$ 31.41万 - 项目类别:
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