Genetic Studies of Optic Atrophy
视神经萎缩的遗传学研究
基本信息
- 批准号:8018455
- 负责人:
- 金额:$ 33.67万
- 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:2009-02-01 至 2013-01-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAnimal ModelAntioxidantsApoptosisApoptosis InhibitorAutosomal Dominant Optic AtrophyBlindnessCaspase InhibitorCell DeathCellsClinicalClinical ResearchCochlear ImplantsColor VisionsColor vision defectDataDegenerative DisorderDepositionDevelopmentDiseaseDrosophila eyeDrosophila genusDynaminEffectivenessEmbryoEvaluationExcisionEyeFamilyFunctional disorderGTP BindingGatekeepingGene MutationGenesGeneticGenetic TechniquesHealthHearingHearing TestsHumanInner mitochondrial membraneKnock-outLeadLinkLongevityMicroscopeMitochondriaMitochondrial Membrane ProteinMitochondrial ProteinsModelingMolecularMotorMutationMutation AnalysisN-terminalNuclearOlder PopulationOptic AtrophyOptic DiskOpticsOrganOrthologous GeneOxidative StressPallorPathogenesisPathway interactionsPatientsPeptide HydrolasesPharmaceutical PreparationsPhenotypePhosphorusPigmentsPlayPopulationPower PlantsPreclinical Drug EvaluationProductionProteinsPublicationsReactive Oxygen SpeciesRecruitment ActivityResearchRespirationRetinal ConeRetinal DegenerationRetinal DiseasesRetinal Ganglion CellsRoleScotomaSensorySignal TransductionSiteStressSuperoxide DismutaseTechnologyTestingTherapeutic AgentsTransmembrane DomainVisual AcuityVitamin Eclinical phenotypeclinically relevantcytochrome cdemographicsflyhearing impairmenthuman subjectimprovedinsightknockout genelensmitochondrial dysfunctionmutantnoveloverexpressionpatient populationpresenilinpreventprogramsresearch clinical testingrhomboidsuperoxide dismutase 1
项目摘要
DESCRIPTION (provided by applicant): Optic atrophy gene 1 (OPA1) is a nuclear gene encoding a mitochondrial protein. Mutation of OPA1 is the most common cause for autosomal dominant optic atrophy (DOA). This condition primarily affects eyes, and is characterized by gradual vision loss, color vision defects, and temporal optic pallor. Previous studies have shown that OPA1 is ubiquitously expressed and serves as a gatekeeper for cytochrome-c release, and is important in mitochondrial fusion and ATP production. To understand the molecular mechanism by which OPA1 mutations cause optic atrophy and to facilitate the development of an effective therapeutic agent for optic atrophies, recently we have generated an Opa1 knockout model in Drosophila. By analyzing phenotypes in the developing and adult Drosophila eyes, we found that the heterozygous mutation of dOpa1, ortholog of human OPA1, caused by a P-element insertion results in no discernable eye phenotype under a microscope, but is instead associated with a shortened lifespan, whereas the homozygous mutation results in embryonic lethality. Taking advantage of the powerful Drosophila genetic techniques, we created eye-specific somatic mutants. The somatic homozygous mutation of dOpa1 in the eyes caused rough (mispatterning) and glossy (decreased lens deposition) eye phenotypes in adult flies, and was reversible by precise excision of the inserted P-element. Moreover, we also show that Superoxide dismutase 1 (SOD1), Vitamin E, and genetically overexpressed human SOD1 (hSOD1) is able to reverse the glossy eye phenotype of dOPA1 mutant large clones, further suggesting that ROS play an important role in cone and pigment cell death. Our preliminary results also show that some OPA1 mutations cause loss of vision, hearing, and other organ abnormalities. The hearing loss is associated with asynchronous cochlear conduction and cochlear implants provide remarkable results to restore hearing. Our central hypothesis is that mutations in OPA1 cause effects in multiple organs. In this study, we will perform mutation analysis on OPA1 with a readily available large patient population and recruit additional patients with optic atrophy if necessary. For patients with known OPA1 mutations, we will perform clinical evaluations to expand the clinical phenotypes, including hearing test, cochlear potential analysis and motor sensory abnormalities (Aim 1). In Aim 2, we will further characterize phenotypes and identify the molecular mechanism by which dOpa1 mutations cause rough eyes. We will analyze the mutants for apoptosis in eye phenotypes and test the effectiveness of caspase inhibitor in reversing rough eye phenotypes. In Aim 3, we will test the molecular mechanisms by which mutation of OPA1 affects the lifespan. Our preliminary results showed that mutation of dOpa1 causes increased production of ROS and poor tolerance to stress. We will examine superoxide dismutase (SOD) activity and mitochondrial respiration rate in our dOpa1 flies. Finally, we will test if antioxidants can rescue the shortened lifespan phenotype. We anticipate that this study will provide novel insights into the pathogenesis of optic atrophy and assist in the development of novel therapies to prevent vision loss. The clinical relevance of the proposed research is strengthened by studying an animal model and human subjects in parallel. Many degenerative retinal diseases share similar clinical features and therefore, the data from this study may be extended to those diseases. PUBLIC HEALTH RELEVANCE: Optic atrophy gene 1 (OPA1) programs proteins found in mitochondria, the power plant of cells in our body. For example we have found that mutations of OPA1 cause optic atrophy as well as hearing loss. We were also surprised to find that Opa1 mutation affects the life span in fly. In this study, we will clinically evaluate patients with known mutation of OPA1 to further expand our understanding of the effects of this gene on other organs. We will closely discern how optic atrophy is caused in fly model. In addition, we can also use this model to screen drug for treatments of optic atrophy. By understanding how Opa1 affect the life span, we may develop a drug to prolong the life span. This study will allow us to understand how mutations of OPA1 cause optic atrophy and explore its novel function in lifespan and provide us a potential opportunity to develop treatments for the disease.
描述(由申请人提供):视神经萎缩基因1 (OPA1)是一个编码线粒体蛋白的核基因。OPA1突变是常染色体显性视神经萎缩(DOA)最常见的原因。这种疾病主要影响眼睛,其特征是逐渐丧失视力、色觉缺陷和暂时性视白。先前的研究表明,OPA1是普遍表达的,是细胞色素c释放的守门人,在线粒体融合和ATP产生中起重要作用。为了了解OPA1突变导致视神经萎缩的分子机制,并促进开发有效的视神经萎缩治疗剂,最近我们在果蝇中建立了一个OPA1敲除模型。通过分析发育和成年果蝇眼睛的表型,我们发现由p元素插入引起的dOpa1杂合突变在显微镜下无法识别眼睛表型,但与寿命缩短有关,而纯合突变导致胚胎致死。dOpa1是人类OPA1的同源物。利用强大的果蝇基因技术,我们创造了眼睛特异性的体细胞突变体。在成年果蝇中,dOpa1的体细胞纯合突变导致了粗糙(图案错误)和光滑(晶状体沉积减少)的眼睛表型,并且通过精确切除插入的p元素可以逆转。此外,我们还发现超氧化物歧化酶1 (SOD1)、维生素E和基因过表达的人类SOD1 (hSOD1)能够逆转dOPA1突变大克隆的亮眼表型,进一步表明ROS在锥体和色素细胞死亡中起重要作用。我们的初步结果还表明,一些OPA1突变会导致视力、听力丧失和其他器官异常。听力损失与耳蜗非同步传导有关,人工耳蜗对听力恢复效果显著。我们的中心假设是,OPA1的突变会对多个器官产生影响。在这项研究中,我们将对现成的大量患者群体进行OPA1突变分析,并在必要时招募额外的视神经萎缩患者。对于已知OPA1突变的患者,我们将进行临床评估以扩大临床表型,包括听力测试、耳蜗电位分析和运动感觉异常(Aim 1)。在Aim 2中,我们将进一步表征表型并确定dOpa1突变导致粗糙眼睛的分子机制。我们将分析突变体在眼表型中的凋亡,并测试caspase抑制剂在逆转粗糙眼表型中的有效性。在Aim 3中,我们将测试OPA1突变影响寿命的分子机制。我们的初步结果表明,dOpa1突变导致ROS的产生增加和对胁迫的耐受性差。我们将在dOpa1果蝇中检测超氧化物歧化酶(SOD)活性和线粒体呼吸速率。最后,我们将测试抗氧化剂是否可以挽救缩短寿命的表型。我们期望这项研究将为视神经萎缩的发病机制提供新的见解,并有助于开发新的治疗方法来预防视力丧失。通过并行研究动物模型和人类受试者,加强了拟议研究的临床相关性。许多退行性视网膜疾病具有相似的临床特征,因此,本研究的数据可能扩展到这些疾病。公共卫生相关性:视神经萎缩基因1 (OPA1)控制线粒体中发现的蛋白质,线粒体是我们体内细胞的发电厂。例如,我们发现OPA1的突变会导致视神经萎缩和听力损失。我们还惊讶地发现,Opa1突变会影响果蝇的寿命。在本研究中,我们将对已知的OPA1突变患者进行临床评估,以进一步扩大我们对该基因对其他器官影响的认识。我们将在果蝇模型中密切观察视神经萎缩是如何引起的。此外,我们还可以利用该模型筛选治疗视神经萎缩的药物。通过了解Opa1如何影响寿命,我们可能会开发出延长寿命的药物。这项研究将使我们了解OPA1突变如何导致视神经萎缩,探索其在寿命中的新功能,并为我们开发治疗该疾病的潜在机会。
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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TAOSHENG HUANG其他文献
TAOSHENG HUANG的其他文献
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{{ truncateString('TAOSHENG HUANG', 18)}}的其他基金
SLC25A46 mutations cause optic atrophy, axonal neuropathy, and cerebellar neurodegeneration
SLC25A46 突变导致视神经萎缩、轴突神经病变和小脑神经变性
- 批准号:
9265469 - 财政年份:2016
- 资助金额:
$ 33.67万 - 项目类别:
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