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：
Ikjae Lee
金额：
$ 22.96万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
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：
https://reporter.nih.gov/project-details/10644489
关键词：
ALS patients Adult Affect Amyotrophic Lateral Sclerosis Area Biological Markers Biometry Blood Body Composition Body Weight Body mass index C9ORF72 Cessation of life Classification Clinic Clinical Clinical Course of Disease Cohort Studies Control Groups Data Data Set Deglutition Disorders Development Diagnosis Diagnostic Differential Diagnosis Disease Disease Progression Early Diagnosis Early Intervention Early identification Early treatment Energy Intake Energy Metabolism Epidemiology Family Fatty acid glycerol esters Foundations Genetic Predisposition to Disease Genetic Risk Goals Height Individual Knowledge Learning Lipids Longitudinal cohort study Machine Learning Measures Mentored Patient-Oriented Research Career Development Award Metabolic Metabolic Marker Metabolism Motor Neuron Disease Motor Neurons Muscle Weakness Natural History Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Newly Diagnosed Oxidative Stress Participant Pathogenesis Pathogenicity Pattern Plasma Population Positioning Attribute Primary Lateral Sclerosis Probability Production Prospective, cohort study Public Health Reporting Research Research Personnel Research Training Respiratory Failure Rest Sampling Signs and Symptoms Stress Symptoms Techniques United States Universities Validation Variant Weight algorithm training biobank biomarker development clinical application cohort comparison control diagnostic biomarker drug development early detection biomarkers effective therapy familial amyotrophic lateral sclerosis fatty acid oxidation indexing insight lipid mediator lipid metabolism lipidome lipidomics longitudinal, prospective study machine learning algorithm metabolic profile mitochondrial dysfunction mutation carrier novel novel diagnostics phenotypic biomarker predictive marker predictive tools prevent skills sporadic amyotrophic lateral sclerosis supervised learning therapeutic target total 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.

项目概要/摘要肌萎缩侧索硬化症 (ALS) 是一种破坏性疾病，会导致上、下运动神经元功能障碍退化导致进行性虚弱，并因吞咽困难和呼吸衰竭而死亡。那里迫切需要开发有效的治疗方法来阻止或逆转进展。然而，这已经证明由于对 ALS 发病机制的不完全了解和诊断的延迟，该研究具有挑战性。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/成分作为临床疾病发生的早期指标。这些标记的识别可以促进早期干预以预防或延缓疾病进展并提供治疗信息目标是具有 ALS 遗传风险的个体。我假设 1）血浆脂质介质（脂质组）可以准确区分 ALS 和原发性侧索硬化症 (PLS) 受试者与对照组 2) 身体 C9orf72+ ALS、症状前 C9orf72 突变携带者之间的体重/成分和 EE 不同 (C9orf72+ Pre-ALS) 参与者和对照 3) 某些代谢特征将预测症状的发生 C9orf72+ ALS 前期参与者。在这项拟议的研究中，我将 1) 研究 ALS 的血浆脂质组谱和 PLS 受试者鉴定脂质介质作为运动神经元疾病的诊断生物标志物，2) 评估 C9orf72+ ALS 和 Pre-ALS 中的体重/成分和 EE，用于测量能量代谢的变化在疾病发生之前和整个疾病过程中，以及 3) 跟踪一组 C9orf72+ Pre-ALS 参与者每年追踪 ALS 症状和体征的出现，以确定某些代谢特征是否可以预测该遗传易感人群中出现症状。该项目的成功完成将提供 1) 建立脂质组谱作为 ALS 和 PLS 的诊断生物标志物的关键数据，2) 提供为 C9orf72+ Pre-ALS 个体的前瞻性队列研究奠定了基础，以确定脂质组谱是否代谢标记（身体成分，EE）可以作为表型的预兆标记从无症状 ALS 转变为有症状 ALS。该 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) 脂质组数据生成和分析方面的专业知识，2) 代谢和 EE 方面的专业知识，以及 3) 掌握用于临床应用的先进统计技术。我将利用我在该领域接受的研究培训 K23 领导一项针对 ALS 前期参与者的纵向队列研究，以确定两者之间的关系 ALS 的代谢变化和临床表现。我的首要目标是确定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来预防或延缓病情 ALS 的进展。