The Omi/HtrA2 Signal Transduction Pathway
Omi/HtrA2 信号转导途径
基本信息
- 批准号:7286271
- 负责人:
- 金额:$ 28.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-09-12 至 2010-08-31
- 项目状态:已结题
- 来源:
- 关键词:AgeApoptoticBindingBiochemical GeneticsBiological ModelsCatalytic DomainCell NucleusCell SurvivalCessation of lifeConditionDNA Sequence RearrangementDiseaseDisruptionEndopeptidasesGenesGenetic TranscriptionHealthHomeostasisHumanKnockout MiceLearningLinkMaintenanceMediatingMicroarray AnalysisMitochondriaMitochondrial ProteinsMolecularMusMuscleMutationNatureNerve DegenerationNeurodegenerative DisordersOmi serine proteaseParkinson DiseasePatientsPeptide HydrolasesPhenotypePhysiologicalPoint MutationProtease DomainProteomicsRegulationResearchRoleSignal TransductionSignal Transduction PathwayStressTissuesTransgenic OrganismsTransmembrane Domainapoptosis inducing factorbasebiological adaptation to stresscytochrome cdaydesigninterestmitochondrial dysfunctionresearch studysensorwasting
项目摘要
DESCRIPTION (provided by applicant): Mitochondrial dysfunction is responsible for many human neurodegenerative diseases. The mechanism by which mitochondria senses and respond to stress is poorly understood. Recent results from our lab and others suggested that the mitochondrial serine protease Omi/HtrA2 is a sensor of mitochondrial stress. Inactivation of Omi/HtrA2 in mnd2 mice due to a point mutation in the protease domain or disruption of the Omi gene in Omi-/- knockout mice leads to neurodegeneration, muscle wasting and death by 40 days of age because of mitochondrial dysfunction. These finding suggests that Omi/HtrA2 has a vital role within the mitochondria that is required for maintenance of mitochondrial homeostasis at normal physiological conditions. Because Omi/HtrA2 shares extensive sequence and structural homology with the bacterial stress sensor DegS, we hypothesize that Omi/HtrA2, like DegS, is a stress sensor that becomes activated when its PDZ domain recognizes exposed PDZ-binding motifs in misfolded mitochondrial proteins. The activated Omi/HtrA2 then triggers a proteolytic cascade that leads to activation of specific stress response genes. The nature of the mitochondrial proteins and the types of unfolding stresses that trigger activation of Omi/HtrA2 are currently unknown. The nature of the mitochondrial Omi/HtrA2 substrates is also unknown. The mnd2 and Omi-/- mice are excellent model systems to study the role of Omi/HtrA2 in cell survival. To investigate the protective function and the signal transduction pathway of Omi/HtrA2, we propose in the first and second specific aims to carry out transgenic rescue experiments in Omi-/- and mnd2 mice to define the role of the PDZ and transmembrane domains of Omi in its protective function. We also propose to study phenotype of specific tissue expression of wildtype Omi in Omi-/- and mnd2 mice. In the remaining specific aims we propose to use biochemical, genetic, and proteomic approaches to identify and characterize the upstream mitochondrial regulators of the PDZ domain of Omi/HtrA2 and the critical mitochondrial substrates of Omi/HtrA2. We predict that Omi/HtrA2-mediated cleavage of a specific mitochondrial substrate could send a signal to the nucleus and activate transcription of Omi/HtrA2-specific stress responsive genes. We propose to identify these genes by microarray analysis. Understanding the molecular basis of stress sensing in the mitochondria and the regulation of the protease activity of Omi/HtrA2 is important for designing strategies for the treatment of mitochondrial-related neurodegenerative diseases. Mutations that reduce the activity of Omi/HtrA2 protease have recently been identified in patients with Parkinson's disease, suggesting a link between Omi/HtrA2 and neurodegeneration in some cases of Parkinson's disease and perhaps other human neurodegenerative diseases. Thus, learning about the function of Omi/HtrA2 under normal and disease conditions is a research objective of clear health interest.
描述(申请人提供):线粒体功能障碍是许多人类神经退行性疾病的原因。线粒体感知和应对压力的机制还知之甚少。本实验室和其他实验室的最新研究结果表明,线粒体丝氨酸蛋白酶Omi/HtrA2是线粒体应激的感受器。在mnd2小鼠中,由于蛋白酶域的点突变或在Omi/-基因敲除小鼠中Omi基因的中断导致Omi/HtrA2的失活,导致神经退化、肌肉萎缩和40天龄前由于线粒体功能障碍而死亡。这些发现表明Omi/HtrA2在线粒体内具有重要作用,这是在正常生理条件下维持线粒体动态平衡所必需的。因为Omi/HtrA2与细菌应激传感器DEGS有广泛的序列和结构上的同源性,我们假设Omi/HtrA2和DEGS一样,是一个应激传感器,当其PDZ结构域识别错误折叠的线粒体蛋白中暴露的PDZ结合基序时,它就会被激活。激活的Omi/HtrA2随后触发蛋白水解级联反应,导致特定应激反应基因的激活。线粒体蛋白的性质和触发Omi/HtrA2激活的去折叠应激类型目前尚不清楚。线粒体Omi/HtrA2底物的性质也不清楚。Mnd2和Omi-/-小鼠是研究Omi/HtrA2在细胞存活中作用的优秀模型系统。为了研究Omi/HtrA2的保护功能和信号转导途径,我们在第一和第二个具体目标中建议在Omi-/-和mnd2小鼠中进行转基因救援实验,以确定Omi的PDZ和跨膜区在其保护功能中的作用。我们还建议研究野生型Omi在Omi-/-和mnd2小鼠中的特异性组织表达的表型。在剩下的特定目标中,我们建议使用生化、遗传学和蛋白质组学方法来鉴定和表征Omi/HtrA2的PDZ结构域的上游线粒体调节因子以及Omi/HtrA2的关键线粒体底物。我们预测,Omi/HtrA2介导的特定线粒体底物的切割可以向细胞核发送信号,并激活Omi/HtrA2特异性应激反应基因的转录。我们建议通过微阵列分析来鉴定这些基因。了解线粒体应激反应的分子基础和Omi/HtrA2蛋白水解酶活性的调节对于设计线粒体相关神经退行性疾病的治疗策略具有重要意义。最近在帕金森病患者中发现了降低Omi/HtrA2蛋白酶活性的突变,这表明在帕金森病的某些病例中,Omi/HtrA2与神经变性之间存在联系,可能还有其他人类神经退行性疾病。因此,了解Omi/HtrA2在正常和疾病条件下的功能是一个明确的健康兴趣的研究目标。
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)
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Emad S Alnemri其他文献
Apoptosis in human monocytic THP.1 cells involves several distinct targets of N-tosyl-L-phenylalanyl chloromethyl ketone (TPCK)
人单核细胞 THP.1 细胞的凋亡涉及 N-甲苯磺酰-L-苯丙氨酰氯甲基酮(TPCK)的几个不同靶点
- DOI:
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1997-10-01 - 期刊:
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Huijun Zhu;David Dinsdale;Emad S Alnemri;Gerald M Cohen - 通讯作者:
Gerald M Cohen
Emad S Alnemri的其他文献
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