Metabolic Alteration in Presymptomatic and Symptomatic ALS Study (MAPS ALS Study)

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。

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.