Regulation of the retinal ganglion cell repair program by the mitochondrial protein Armcx1
线粒体蛋白 Armcx1 对视网膜神经节细胞修复程序的调节
基本信息
- 批准号:10558710
- 负责人:
- 金额:$ 39.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAffectArmadillo RepeatAxonBindingBiologyCell SurvivalChronicChronic DiseaseCytosolDataDevelopmentDiseaseDisease modelDown-RegulationElementsEtiologyFunctional disorderGoalsImpairmentInterventionKnowledgeLengthLinkMass Spectrum AnalysisMitochondriaMitochondrial ProteinsModelingMolecular ConformationNatural regenerationNerve CrushNerve DegenerationNeurodegenerative DisordersNeuronsOptic NerveOptic Nerve InjuriesOuter Mitochondrial MembranePathologicPathologyPharmacologic SubstancePhasePhysiologicalPlayProcessProteinsRegulationResearchRetinal DiseasesRetinal Ganglion CellsRoleStressTestingTherapeuticTraumatic injuryVision DisordersWorkarmaxon growthaxon regenerationin vivoinnovationknock-downlink proteinmitochondrial dysfunctionneuronal cell bodyneuroprotectionnoveloptic nerve disorderoverexpressionprogramsprotein protein interactionproteomic signaturerepairedretinal ganglion cell degeneration
项目摘要
Abstract
Retinal ganglion cells (RGCs), like most neurons, heavily rely on functions fulfilled by
mitochondria. However, for unclear reasons the sensitivity of RGCs to mitochondrial dysfunction is
higher than in others neuronal types. As a result, many blinding diseases that affect
RGCs are accompanied by mitochondrial impairment. These diseases have very different etiologies
but likely share a common pathophysiology that involves some aspect of mitochondrial
biology. Nevertheless, we have little knowledge of the processes that regulate RGC
mitochondria in vivo which has impeded the development of mitochondria-directed treatments to
promote RGC repair. It is important therefore to understand how RGCs regulate mitochondrial
function and dynamics in vivo as a step in defining regulatory nodes amenable to
pharmaceutical intervention. RGC axons appear to be a prime target for these interventions as they
are especially sensitive to degenerative stress. In these axons that extend to a considerable
distance, it is crucial that mitochondria are appropriately distributed to serve the needs of the
periphery. We recently highlighted the importance of this distribution for RGC repair.
We demonstrated that increasing mitochondrial transport protects RGCs from degeneration and promote
axonal regeneration (Cartoni et al. 2016). This study uncovered a key regulator of
mitochondrial transport; a mammalian specific mitochondrial protein called Armadillo
Repeat-Containing X Linked Protein 1 (Armcx1). We showed that it regulates axonal
mitochondrial transport and that it is both necessary and sufficient for RGC survival
and axonal regeneration after optic nerve injury. These findings suggest that Armcx1
controls the mitochondrial distribution of a mitochondria based RGC repair program. Our long-term
research goal is to elucidate and manipulate the elements of this newly identified
repair program to treat vision disorders. Despite the importance of Armcx1 in RGC repair after
traumatic injury, little is known about the physiological functions of Armcx1 in healthy and
diseased RGCs. Our overall objective is to evaluate how Armcx1 impacts RGC degeneration and repair
as well as to decipher how this protein regulates mitochondrial dynamics and function.
Based on our preliminary results, our central hypothesis is that Armcx1 regulates
mitochondrial transport in demanding conditions such as diseases and/or axonal outgrowth.
Specifically, we hypothesize that Armcx1 is a ubiquitous player in neuroprotection (Aim 1) and that
it is a critical component of the normal RGC axonal outgrowth program (Aim 2). Finally, in an
effort to understand the mechanism by which mitochondria promote RGC repair, we will analyze the
axonal and somatic mitoproteome and identify direct and indirect Armcx1-binding partners in vivo
(Aim 3).
摘要
像大多数神经元一样,视网膜神经节细胞(RGC)严重依赖于
线粒体。然而,由于不明原因,视网膜节细胞对线粒体功能障碍的敏感性是
高于其他神经细胞类型。因此,影响人类健康的许多致盲疾病
视网膜节细胞伴有线粒体损伤。这些疾病有非常不同的病因
但很可能有共同的病理生理学,涉及线粒体的某些方面
生物学。然而,我们对监管研资局的程序知之甚少。
体内的线粒体,阻碍了线粒体导向治疗的发展
促进研资局修复。因此,了解视网膜节细胞如何调节线粒体是很重要的。
体内的功能和动力学,作为定义服从于
药物干预。RGC轴突似乎是这些干预的主要目标,因为它们
对退化压力特别敏感。在这些轴突中,延伸到相当大的
距离,线粒体的适当分布是至关重要的,以服务于
外围设备。我们最近强调了这种分配对研资局修复的重要性。
我们证明,增加线粒体转运可以保护视网膜节细胞免于退化,并促进
轴突再生(Cartoni et al.2016)。这项研究揭示了一个关键的调节因子
线粒体运输;一种哺乳动物特有的线粒体蛋白,称为Armadillo
含重复序列的X连锁蛋白1(Armcx1)。我们证明了它可以调节轴突
线粒体运输是RGC生存的必要条件和充分条件
视神经损伤后轴突再生。这些发现表明,Armcx1
控制基于线粒体的RGC修复程序的线粒体分布。我们的长期合作
研究目标是阐明和操纵这一新发现的
治疗视力障碍的修复计划。尽管Armcx1在RGC修复中的重要性
创伤性损伤,对Armcx1在健康和健康人群中的生理功能知之甚少
患病的视网膜节细胞。我们的总体目标是评估Armcx1对RGC退变和修复的影响
以及破译这种蛋白质如何调节线粒体的动力学和功能。
根据我们的初步结果,我们的中心假设是Armcx1调节
线粒体在疾病和/或轴突生长等苛刻条件下的运输。
具体地说,我们假设Armcx1在神经保护方面是一个无处不在的参与者(目标1),并且
它是正常的RGC轴突生长计划(目标2)的关键组成部分。最后,在一个
为了了解线粒体促进RGC修复的机制,我们将分析
轴突和体细胞有丝分裂蛋白质组与体内Armcx1直接和间接结合伙伴的鉴定
(目标3)。
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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Sidney M Gospe其他文献
The first inborn error of manganese metabolism caused by mutations in SLC30A10, a newly identified manganese transporter
由新发现的锰转运蛋白 SLC30A10 突变引起的第一个先天性锰代谢错误
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
K. Tuschl;Peter E. Clayton;Sidney M Gospe;G. Shamshad;Shahnaz Ibrahim;P. Singhi;R. T. Ribeiro;Zaki;M. L. D. Rosario;Sarah Dyack;V. Price;R. Wevers;Pb Mills - 通讯作者:
Pb Mills
Prenatal Exposure to Toluene Results in Abnormal Neuronal Proliferation and Migration
产前暴露于甲苯会导致神经元增殖和迁移异常
- DOI:
10.1203/00006450-199904020-02031 - 发表时间:
1999-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Sidney M Gospe;Shan Shan Zhou - 通讯作者:
Shan Shan Zhou
Sidney M Gospe的其他文献
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{{ truncateString('Sidney M Gospe', 18)}}的其他基金
In Vivo Modeling of Mitochondrial Complex I Deficiency in Retinal Ganglion Cells
视网膜神经节细胞线粒体复合物 I 缺陷的体内建模
- 批准号:
10329943 - 财政年份:2018
- 资助金额:
$ 39.15万 - 项目类别:
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