Metabolic Alteration in Presymptomatic and Symptomatic ALS Study (MAPS ALS Study)
症状前和症状性 ALS 研究中的代谢改变(MAPS ALS 研究)
基本信息
- 批准号:10644489
- 负责人:
- 金额:$ 22.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-01 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:ALS patientsAdultAffectAmyotrophic Lateral SclerosisAreaBiological MarkersBiometryBloodBody CompositionBody WeightBody mass indexC9ORF72Cessation of lifeClassificationClinicClinicalClinical Course of DiseaseCohort StudiesControl GroupsDataData SetDeglutition DisordersDevelopmentDiagnosisDiagnosticDifferential DiagnosisDiseaseDisease ProgressionEarly DiagnosisEarly InterventionEarly identificationEarly treatmentEnergy IntakeEnergy MetabolismEpidemiologyFamilyFatty acid glycerol estersFoundationsGenetic Predisposition to DiseaseGenetic RiskGoalsHeightIndividualKnowledgeLearningLipidsLongitudinal cohort studyMachine LearningMeasuresMentored Patient-Oriented Research Career Development AwardMetabolicMetabolic MarkerMetabolismMotor Neuron DiseaseMotor NeuronsMuscle WeaknessNatural HistoryNerve DegenerationNeurodegenerative DisordersNeuronal DysfunctionNewly DiagnosedOxidative StressParticipantPathogenesisPathogenicityPatternPlasmaPopulationPositioning AttributePrimary Lateral SclerosisProbabilityProductionProspective, cohort studyPublic HealthReportingResearchResearch PersonnelResearch TrainingRespiratory FailureRestSamplingSigns and SymptomsStressSymptomsTechniquesUnited StatesUniversitiesValidationVariantWeightalgorithm trainingbiobankbiomarker developmentclinical applicationcohortcomparison controldiagnostic biomarkerdrug developmentearly detection biomarkerseffective therapyfamilial amyotrophic lateral sclerosisfatty acid oxidationindexinginsightlipid mediatorlipid metabolismlipidomelipidomicslongitudinal, prospective studymachine learning algorithmmetabolic profilemitochondrial dysfunctionmutation carriernovelnovel diagnosticsphenotypic biomarkerpredictive markerpredictive toolspreventskillssporadic amyotrophic lateral sclerosissupervised learningtherapeutic targettotal energy expenditure
项目摘要
Project Summary/Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating disease with upper and lower motor neuron dysfunction
and degeneration leading to progressive weakness and death due to dysphagia and respiratory failure. There
is an urgent need to develop effective treatment to stop or reverse the progression. However, this has proven
to be challenging due to an incomplete understanding of the pathogenesis and delay in the diagnosis of ALS.
There are data supporting biomarkers of mitochondrial dysfunction, energy expenditure (EE) and body
weight/composition as early indices of incident clinical disease. Identification of these markers could facilitate
earlier intervention to prevent or delay disease progression as well as provide information on therapeutic
targets in individuals at genetic risk for ALS. I hypothesize that 1) the plasma lipid mediators (lipidome) can
accurately differentiate ALS, and primary lateral sclerosis (PLS) subjects from controls 2) body
weight/composition and EE differ between C9orf72+ ALS, presymptomatic C9orf72 mutation carriers
(C9orf72+ Pre-ALS) participants and controls 3) certain metabolic profiles will predict symptom onset in
C9orf72+ Pre-ALS participants. In this proposed study, I will 1) investigate the plasma lipidome profile of ALS
and PLS subjects to identify lipid mediators as diagnostic biomarkers in motor neuron disease, 2) evaluate
body weight/composition and EE in C9orf72+ ALS and Pre-ALS to measure changes in energy metabolism
in advance of and through the course of disease, and 3) follow a cohort of C9orf72+ Pre-ALS participants
annually to track the emergence of ALS symptoms and signs to determine if certain metabolic profiles predict
symptom onset in this genetically predisposed population. Successful completion of this project would provide
key data to 1) establish the lipidome profile as a diagnostic biomarker for ALS and PLS, and 2) provide the
foundation for a prospective cohort study of C9orf72+ Pre-ALS individuals to determine if the lipidome profile
and metabolic markers (body composition, EE) could serve as a premonitory marker for the phenotypic
conversion from asymptomatic to symptomatic ALS. This K23 award will provide the support needed to
complete the proposed research and to further develop my expertise in three major scientific areas, 1)
expertise in lipidome data production and analysis, 2) expertise in metabolism and EE, and 3) mastery of
advanced statistical techniques for clinical applications. I will leverage the research training I receive in the
K23 to lead a longitudinal cohort study of pre-ALS participants to determine the relationship between
metabolic changes and clinical manifestations of ALS. My overarching goal is to identify early diagnostic
biomarkers and therapeutic targets for the development of an effective treatment to prevent or delay the
progression of ALS.
项目摘要/摘要
肌萎缩侧索硬化症(ALS)是一种伴有上下运动神经元功能障碍的破坏性疾病
和退化导致进行性虚弱和死亡,由于吞咽困难和呼吸衰竭。那里
迫切需要开发有效的治疗方法来阻止或逆转这种进展。然而,这证明了
由于对肌萎缩侧索硬化症发病机制的不完全了解和诊断的延误,这是一个具有挑战性的问题。
有数据支持线粒体功能障碍、能量消耗(EE)和身体的生物标志物
体重/成分作为临床发病的早期指标。识别这些标记可以帮助
早期干预以预防或延缓疾病进展,并提供治疗信息
具有ALS遗传风险的个体的靶点。我假设1)血浆中的脂质介体(脂质体)可以
准确区分肌萎缩侧索硬化症和原发性侧索硬化症患者与对照组2)
症状前C9orf72突变携带者C9orf72+ALS的体重/成分和EE差异
(C9ORF72+肌萎缩侧索硬化症前期)参与者和对照组3)某些代谢特征将预测症状在
C9ORF72+ALS前期患者。在这项拟议的研究中,我将1)调查ALS患者的血浆脂质体谱
和偏最小二乘法确定脂质介质作为运动神经元病的诊断生物标志物,2)评价
C9orf72+肌萎缩侧索硬化症和肌萎缩侧索硬化症前期患者的体重/成分和EE测定能量代谢的变化
在疾病之前和整个病程中,以及3)跟踪C9orf72+ALS前期参与者的队列
每年追踪肌萎缩侧索硬化症症状和体征的出现,以确定某些代谢特征是否可以预测
在这一遗传易感人群中出现症状。该项目的成功完成将提供
关键数据:1)建立脂质体谱作为ALS和PLS的诊断生物标记物;2)提供
C9orf72+肌萎缩侧索硬化症前期人群的前瞻性队列研究的基础,以确定脂质体谱
代谢标志物(体成分,EE)可作为表型的先兆标志物
从无症状到有症状的肌萎缩侧索硬化症的转变。这项K23奖项将提供所需的支持,
完成拟议的研究,并进一步发展我在三个主要科学领域的专业知识,1)
脂组数据生产和分析方面的专业知识,2)新陈代谢和EE方面的专业知识,以及3)掌握
临床应用的先进统计技术。我将利用我在
K23领导对肌萎缩侧索硬化症前期参与者进行纵向队列研究,以确定两者之间的关系
肌萎缩侧索硬化症的代谢变化及临床表现我的首要目标是识别早期诊断
生物标志物和治疗靶点,用于开发有效的治疗方法,以预防或延缓
肌萎缩侧索硬化的进展。
项目成果
期刊论文数量(0)
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