MITOCHONDRIAL ENCEPHALOMYOPATHIES: APPROACHES TO TREATMENT
线粒体脑肌病:治疗方法
基本信息
- 批准号:8741702
- 负责人:
- 金额:$ 162.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-30 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnabolismAreaAwarenessBasic ScienceBiochemicalBiochemistryBiological MarkersBiopsyBloodBostonBypassCellular biologyCerebrumClinicalClinical PathologyClinical ResearchCoenzyme Q10CollaborationsConsultationsDevelopmentDiseaseDoctor of PhilosophyEffectivenessEnzymesEquipmentExposure toFundingGeneticGenetic screening methodHistocytochemistryHumanIn VitroIndividualIntentionKnock-in MouseLactic AcidosisLeadershipLongevityMELASMagnetic Resonance SpectroscopyMembraneMitochondriaMitochondrial DNAMitochondrial DiseasesMitochondrial EncephalomyopathiesMolecularMolecular GeneticsMusMuscleMutant Strains MiceNational Institute of Child Health and Human DevelopmentNational Institute of Neurological Disorders and StrokeNatural HistoryNeurologyOnset of illnessOralOutcome MeasurePathologyPhenotypePoint MutationPublic HealthQuality ControlResearchResearch PersonnelRespiratory ChainServicesSkeletal MuscleStrokeSuggestionSyndromeTestingTherapeuticTranslational ResearchUniversitiesadeno-associated viral vectoranalogbasecohortcomparative efficacyeffective therapyfunctional outcomesgene therapyhuman TK2 proteinhuman diseasehuman subjectidebenoneinnovationinterestmetabolomicsoverexpressionpara-Hydroxybenzoic Acidspreventprobandprofessorprogramspublic health relevancesoundtissue culturetool
项目摘要
DESCRIPTION (provided by applicant): Mitochondrial Encephalomyopathies: Approaches to Treatment. Mitochondrial encephalomyopathies are a heavy public health burden and therapy is woefully inadequate. We are proposing therapy-directed studies for disorders associated with mitochondrial DNA (mtDNA) point mutations, especially mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes (MELAS-3243), and for mendelian disorders, including the mtDNA depletion due to TK2 deficiency and coenzyme Q10 (CoQ10) deficiencies. In Project # I, Dr. Darryl De Vivo, P.I. will continue to characterize the natural history of MELAS, correlating clinical course in probands and carriers with cerebral and muscle biomarkers assessed by MRSI and 31P- NMR. He will seek new biomarkers by applying metabolomics (collaboration with Dr. Vamsi Mootha, Harvard University and MIT, Boston, MA). Project #2 (Dr. Eric A. Schon, P.I.) will concentrate on pharmacological approaches to mtDNA-related disorders by evaluating the effectiveness of compounds affecting heteroplasmic shifting or functional rescuing through modulation of mitophagy and quality control. Project # 3 (Dr. Michio Hirano, P.I.) will use pharmacological and gene therapy of thymidine kinase 2 (TK2) deficiency in mice that faithfully recapitulate the human disease. A molecular bypass therapy is showing promising preliminary results, with amelioration of the abnormal phenotype and extension of the lifespan not only in mice but also in a few human subjects. In TK2 knock-in mice he also plans to test gene therapy using adeno- associated virus (AAV) vectors to deliver human TK2 and restore enzymatic activity. In Project # 4 (Dr. Catarina Quinzii, PI), Dr. Quinzii will test genetic and pharmacologic therapies for CoQ10 deficiency in vitro through ADCK3 overexpression and exposure to analogs of 4-hydroxybenzoic acid, a precursor required for CoQ10 biosynthesis. She also proposes to compare efficacies of oral and intrathecal administration of CoQ10 and idebenone in preventing or delaying the molecular and biochemical abnormalities, and the clinical onset of the disease in the Pdss2kd/kd and in the newly available Coq9X/X mutant mice Core Unit A (the Administrative Core) (Dr. Salvatore DiMauro, Director; Dr.Michio Hirano, Co-Director) will provide direction, administration, and external consultation. Core Unit B (the Technical Core) (Dr. Ali Naini, Director) will provide technical service (tissue culture), diagnostc tools (histochemistry, biochemistry, molecular genetics), and manage shared equipment for the project as a whole.
描述(由申请人提供):线粒体脑膜病:治疗方法。线粒体脑膜病是一种沉重的公共卫生负担,治疗严重不足。我们正在提出有关与线粒体DNA(mtDNA)点突变相关的疾病的治疗指导的研究,尤其是线粒体脑瘤性疾病,乳酸性酸中毒和诸如发作(Melas-3243)的中风(Melas-3243),以及包括Mendelian的疾病,包括MTDNA Depletion应得的TK2 Defetienty及其TK2 Defetienty and Tk2 Defetiedial and Tk2 Defitiedils辅酶Q10(COQ10)缺陷。在项目#I中,Darryl de Vivo博士,P.I。 MRSI和31p-NMR评估的脑和载体生物标志物将继续表征Melas的自然史,将临床和携带者的临床过程与临床过程相关联。他将通过应用代谢组学寻求新的生物标志物(与哈佛大学的Vamsi Mootha博士和马萨诸塞州波士顿的MIT合作)。项目#2(Eric A. Schon博士,P.I。)将通过评估影响异质转移或通过调节有线噬菌体和质量控制的化合物的有效性来关注MTDNA相关性疾病的药理方法。 Project#3(Michio Hirano,P.I。)将在小鼠中使用胸苷激酶2(TK2)缺乏症的药理学和基因疗法,以忠实地概括人类疾病。分子旁路疗法显示出令人鼓舞的初步结果,不仅在小鼠中而且在少数人类受试者中,异常表型和寿命的延伸。在TK2敲门小鼠中,他还计划使用腺相关病毒(AAV)向量测试基因治疗,以提供人类TK2并恢复酶活性。在项目#4(Catarina Quinzii博士,PI)中,Quinzii博士将通过ADCK3过表达测试遗传和药理学疗法,以确保COQ10缺乏体外,并暴露于4-羟基苯甲酸的类似物中,这是COQ10生物合理所需的前体。她还建议比较COQ10和IDEBENONE的口服和鞘内给药的疗效,以防止或延迟分子和生化异常,以及在PDSS2KD/KD中疾病的临床发作,以及在新的可用的COQ9X/X突变小鼠A中(行政核心)(校长Salvatore Dimauro博士;联合主任Michio Hirano博士)将提供指导,管理和外部咨询。核心单元B(技术核心)(主管Ali Naini博士)将提供技术服务(组织文化),诊断工具(组织化学,生物化学,分子遗传学),并管理整个项目的共享设备。
项目成果
期刊论文数量(0)
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SALVATORE DIMAURO其他文献
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{{ truncateString('SALVATORE DIMAURO', 18)}}的其他基金
MITOCHONDRIAL ENCEPHALOMYOPATHIES: APPROACHES TO TREATMENT
线粒体脑肌病:治疗方法
- 批准号:
9121387 - 财政年份:2014
- 资助金额:
$ 162.32万 - 项目类别:
North American Mitochondrial Disease Consortium (NAMDC)
北美线粒体疾病联盟 (NAMDC)
- 批准号:
8339450 - 财政年份:2011
- 资助金额:
$ 162.32万 - 项目类别:
North American Mitochondrial Disease Consortium (NAMDC)
北美线粒体疾病联盟 (NAMDC)
- 批准号:
8537981 - 财政年份:2011
- 资助金额:
$ 162.32万 - 项目类别:
North American Mitochondrial Disease Consortium (NAMDC)
北美线粒体疾病联盟 (NAMDC)
- 批准号:
8283495 - 财政年份:2011
- 资助金额:
$ 162.32万 - 项目类别:
DEVELOPING A NORTH AMERICAN MITOCHONDRIAL DISEASE CONSORTIUM (NAMDC)
发展北美线粒体疾病联盟 (NAMDC)
- 批准号:
7938596 - 财政年份:2009
- 资助金额:
$ 162.32万 - 项目类别:
DEVELOPING A NORTH AMERICAN MITOCHONDRIAL DISEASE CONSORTIUM (NAMDC)
发展北美线粒体疾病联盟 (NAMDC)
- 批准号:
7830838 - 财政年份:2009
- 资助金额:
$ 162.32万 - 项目类别:
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