Mitochondrial Protection in Glaucomatous Optic Neuropathy
青光眼视神经病变中的线粒体保护
基本信息
- 批准号:10376972
- 负责人:
- 金额:$ 10.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:A kinase anchoring proteinAddressAdenosine TriphosphateAffectAge-YearsApoptosisApoptoticAxonBioenergeticsBlindnessCalcineurinCalciumCell DeathCell SurvivalComplementComplexCyclic AMPCyclic AMP-Dependent Protein KinasesCytoprotectionDiseaseDynaminElectron Transport Complex IIIFunctional disorderGap JunctionsGenetic PolymorphismGlaucomaGlutamatesGoalsHomeostasisImpairmentIndividualLeadLinkMediatingMetabolic stressMitochondriaModelingNerve DegenerationNeuronsOptic NerveOuter Mitochondrial MembraneOxidasesOxidative PhosphorylationOxidative StressPathogenesisPerformancePeriodicityPhosphorylationPhysiologic Intraocular PressurePlayPrimary Open Angle GlaucomaProductionPropertyProtein DephosphorylationProteinsRespirationRetinaRetinal Ganglion CellsRoleSignal PathwaySignal TransductionSiteStressStructureSuccinate dehydrogenase (ubiquinone)SuperoxidesSynapsesTestingTherapeuticVisionVisual PathwaysVisual impairmentVisual system structurecomplex IVcytochrome c oxidaseexcitotoxicityimprovedinfancymitochondrial dysfunctionneuroprotectionoptic nerve disorderoverexpressionpreservationprotective effect
项目摘要
Glaucoma is a leading cause of blindness worldwide in individuals 60 years of age and older. Glaucomatous
neurodegeneration is associated with impaired mitochondrial network, oxidative stress and mitochondrial
dysfunction. Primary open angle glaucoma, in particular, is linked to polymorphism of mitochondrial cytochrome
c oxidase (COX) subunit I of the oxidative phosphorylation (OXPHOS) complex (Cx)-IV and impaired OXPHOS
Cx-I-linked respiration activity and adenosine triphosphate (ATP) synthesis. Therefore a role for compromised
OXPHOS in pathogenesis of glaucoma is suggested, although the contribution of an impaired mitochondrial
network to glaucoma is poorly understood. A-kinase anchoring protein 1 (AKAP1) is an outer mitochondrial
membrane-targeted AKAP that regulates mitochondrial dynamics and contributes to mitochondrial network,
bioenergetics and calcium homeostasis. Recently, our group has discovered that neuronal AKAP1 has potent
neuroprotective properties through inhibition of mitochondrial fission dynamin-related protein 1 (Drp1), which
suggests that modulation of AKAP1 could be a therapeutic approach to mitochondrial dysfunction and
glaucomatous neurodegeneration. Our preliminary studies showed that 1) elevated intraocular pressure (IOP)
induced loss of AKAP1, activation of calcineurin (CaN) and dephosphorylation of Drp1 at Ser637; 2) loss of
AKAP1 increased CaN and total Drp1 level, and decreased Drp1 phosphorylation at Ser637 in the retina; 3) loss
of AKAP1 further triggered mitochondrial fragmentation and loss, and induced mitophagosome formation in
retinal ganglion cells (RGCs); 4) loss of AKAP1 deregulated OXPHOS Cxs by increasing Cx-II and decreasing
Cx-III-V in the retina, leading to metabolic and oxidative stress; 5) loss of AKAP1 decreased Akt phosphorylation
and activated the Bim/Bax signaling pathway in the retina; and 6) overexpression of AKAP1 led to enhanced
mitochondrial activity and blocked apoptosis in RGCs, and promoted RGC survival in the setting of oxidative
stress. Altogether, these findings suggest a critical role of AKAP1 in RGC protection and lead us to hypothesize
that AKAP1 overexpression protects RGCs from the effects of glaucoma by promoting mitochondrial network,
bioenergetics and structural integrity. We will test whether AKAP1 deficiency and its disruption of the signaling
nexus impinging on mitochondria contribute to the impairment of mitochondrial bioenergetics and structure in
RGCs. We will also test the protective effect of AKAP1 overexpression on mitochondrial bioenergetics and
structure in glaucomatous RGCs and the therapeutic potential of AKAP1 overexpression on the central visual
pathway and vision. We anticipate that these studies will enhance understanding of how AKAP1 regulates
mitochondrial transport, network dynamics and bioenergetics and will support AKAP1 overexpression as a
strategy to induce neuroprotection against glaucoma and optic neuropathies by improving central visual pathway
functions and vision.
青光眼是全球60岁及以上人群致盲的主要原因。青光眼的
项目成果
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{{ truncateString('WONKYU JU', 18)}}的其他基金
Development of AAV-AIBP for neuroprotection in glaucoma
用于青光眼神经保护的 AAV-AIBP 的开发
- 批准号:
10680277 - 财政年份:2023
- 资助金额:
$ 10.93万 - 项目类别:
Mitochondrial Protection in Glaucomatous Optic Neuropathy
青光眼视神经病变中的线粒体保护
- 批准号:
10667427 - 财政年份:2020
- 资助金额:
$ 10.93万 - 项目类别:
Mitochondrial Protection in Glaucomatous Optic Neuropathy
青光眼视神经病变中的线粒体保护
- 批准号:
10441589 - 财政年份:2020
- 资助金额:
$ 10.93万 - 项目类别:
Mitochondrial Protection in Glaucomatous Optic Neuropathy
青光眼视神经病变中的线粒体保护
- 批准号:
10241476 - 财政年份:2020
- 资助金额:
$ 10.93万 - 项目类别:
Mitochondrial Protection in Glaucomatous Optic Neuropathy
青光眼视神经病变中的线粒体保护
- 批准号:
10610198 - 财政年份:2020
- 资助金额:
$ 10.93万 - 项目类别:
Mitochondrial Protection in Glaucomatous Optic Neuropathy
青光眼视神经病变中的线粒体保护
- 批准号:
10035019 - 财政年份:2020
- 资助金额:
$ 10.93万 - 项目类别:
Mitochondrial Protection in Glaucomatous Optic Neuropathy
青光眼视神经病变中的线粒体保护
- 批准号:
10711446 - 财政年份:2020
- 资助金额:
$ 10.93万 - 项目类别:
Mitochondrial Dysfunction in Glaucomatous Optic Neuropathy
青光眼视神经病变中的线粒体功能障碍
- 批准号:
9464735 - 财政年份:2009
- 资助金额:
$ 10.93万 - 项目类别:
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