Project #1 - MELAS-3243: Natural history, functional outcome measures, and predic

项目

基本信息

批准号：
8741705
负责人：
DARRYL C DE VIVO
金额：
$ 46.24万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
https://reporter.nih.gov/project-details/8741705
关键词：
Accounting Anabolism Automobile Driving Base of the Brain Bioenergetics Biological Markers Body Fluids Brain Cell Energetics Cells Choline Clinical Complement Creatine Data Diagnosis Disease Disease Progression Encephalopathies Family Foundations Functional disorder Human Intervention Lactic Acidosis Lead Life Longitudinal Studies MELAS MELAS Syndrome Matched Group Measures Membrane Metabolic Mitochondrial DNA Mitochondrial Diseases Mitochondrial Encephalomyopathies Mitochondrial Myopathies Monitor Mutation N-acetylaspartate Natural History Neurons Outcome Measure Participant Patients Phenotype Phosphocreatine Phospholipids Phosphorus Plasma Point Mutation Predictive Value Protein Biosynthesis Protons Relative (related person)Respiratory Chain Risk Sampling Staging Stroke Syndrome Therapeutic Uncertainty Urine Validation acronyms base effective therapy follow-up functional outcomes in vivo indexing inorganic phosphate magnetic resonance spectroscopic imaging metabolomics mitochondrial DNA mutation mitochondrial dysfunction multidisciplinary mutation carrier neuroimaging novel outcome forecast phosphodiester phosphomonoester programs response

Accounting Anabolism Automobile Driving Base of the Brain Bioenergetics Biological Markers Body Fluids Brain Cell Energetics Cells Choline Clinical Complement Creatine Data Diagnosis Disease Disease Progression Encephalopathies Family Foundations Functional disorder Human Intervention Lactic Acidosis Lead Life Longitudinal Studies MELAS MELAS Syndrome Matched Group Measures Membrane Metabolic Mitochondrial DNA Mitochondrial Diseases Mitochondrial Encephalomyopathies Mitochondrial Myopathies Monitor Mutation N-acetylaspartate Natural History Neurons Outcome Measure Participant Patients Phenotype Phosphocreatine Phospholipids Phosphorus Plasma Point Mutation Predictive Value Protein Biosynthesis Protons Relative (related person)Respiratory Chain Risk Sampling Staging Stroke Syndrome Therapeutic Uncertainty Urine Validation acronyms base effective therapy follow-up functional outcomes in vivo indexing inorganic phosphate magnetic resonance spectroscopic imaging metabolomics mitochondrial DNA mutation mitochondrial dysfunction multidisciplinary mutation carrier neuroimaging novel outcome forecast phosphodiester phosphomonoester programs response

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项目摘要

Project Summary In 1984, we described two patients with "Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes".1 We proposed the acronym MELAS for this newly described distinctive clinical entity, and speculated about maternal non-Mendelian inheritance, and a mitochondrial DNA (mtDNA) mutation disturbing synthesis of proteins embedded in the respiratory chain. Six years later, Goto and colleagues identified a point mutation in mtDNA (m.3243A>G) of MELAS patients.2 This mutation now accounts for 80% of MELAS cases (commonly referred to as MELAS/3243). For two decades, our team has conducted a long-term longitudinal study of MELAS/3243 patients, establishing a strong foundation in terms of natural history, outcome measures, and biomarkers. However, since there are no clearly validated biomarkers for predicting the risk of conversion, prodromal and mildly symptomatic family relatives continue to live with the uncertainty of converting to the severe MELAS phenotype. This reality emphasizes the need to expand our nascent observations about the natural history of MELAS and the predictive value of brain biomarkers. Our strategies are based on (Specific Aim #1) the need to replicate, using 1H MRSI, our highly promising, preliminary observations of abnormal levels of lactate, NAA, tCr and tCho, in 100 mutation carriers and 30 group-matched healthy control subjects, first at baseline and then again at 2-year follow-up; (Specific Aim #2) the need to measure, using 31P MRSI in synchrony with 1H MRSI, brain levels of (a) phosphocreatine (PCr) to complement and corroborate tCr levels, measured by 1H MRSI, as a marker of cell energetics; b) ATP, to complement and corroborate the 1H MRSI measures of NAA and lactate as indices of mitochondrial dysfunction; c) phosphomonoesters (PME) and phosphodiesters (PDE), to complement and corroborate tCho levels, measured by 1H MRSI, as indices of membrane biosynthesis and turnover, and (d) inorganic phosphate (Pi) as an index of intracellular pH; and (Specific Aim #3) the need to measure temporally concordant levels of metabolite biomarkers in the plasma and urine samples collected from all 130 participants. These three Aims will strengthen our earlier findings of predictive neuroimaging biomarkers, inform us of brain mechanisms underlying metabolic and clinical disturbances, and provide complementary plasma and urine metabolites that, if correlated with the brain biomarkers, will serve as less expensive and more accessible biomarkers predicting risk of conversion to the severe MELAS phenotype.

项目摘要 1984年，我们描述了两名患者“线粒体肌病，脑病，乳酸酸中毒，和类似中风的情节” .1我们提出了这个新描述的独特描述的首字母缩写词临床实体，并推测出母体非孟德尔遗传和线粒体DNA （mtDNA）突变干扰植入呼吸链中的蛋白质的合成。六年后，Goto 同事确定了Melas患者的mtDNA（M.3243a> g）中的一个点突变。2现在这种突变占MELAS病例的80％（通常称为Melas/3243）。二十年来，我们的团队已经对Melas/3243例患者进行了长期纵向研究，在自然历史，结果度量和生物标志物的条款。但是，由于没有明确的验证生物标志物预测转化，前驱和轻度症状的家庭亲戚的风险继续生活在转化为严重的Melas表型的不确定性。这个现实强调扩大我们对Melas自然历史和预测价值的新生观察的需求脑生物标志物。我们的策略是基于（特定目的＃1）使用1H MRSI复制的需要我们对乳酸异常，NaA，TCR和TCHO的高度有希望的初步观察，在100 突变载体和30个组匹配的健康对照组，首先在基线时，然后在2年再次随访；（特定目的＃2）需要测量，使用31p MRSI与1H MRSI同步，大脑（a）磷酸氨酸（PCR）的水平以1H MRSI测量，以补充和证实TCR水平细胞能量学的标记； b）ATP，以补充和证实NAA和NAA的MRSI措施乳酸作为线粒体功能障碍的指标； c）磷光植物（PME）和磷酸化剂（PDE），通过1H MRSI测量的补充和证实TCHO水平，作为膜生物合成指标和（d）无机磷酸盐（PI）作为细胞内pH的指数；（特定目标＃3）需要测量血浆和尿液中代谢物生物标志物的时间一致性水平从所有130名参与者那里收集的样品。这三个目标将加强我们先前的发现预测性神经成像生物标志物，将代谢和临床的脑机制告知我们干扰，并提供互补的血浆和尿液代谢物，如果与大脑相关生物标志物将是便宜且更容易获得的生物标志物，可预测转换为严重的Melas表型。