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

项目总结/摘要 肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种以上、下运动神经元功能障碍为主要表现的破坏性疾病 和变性，导致进行性虚弱和由于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发病机制的不完全理解和诊断延迟，因此具有挑战性。 有数据支持线粒体功能障碍、能量消耗（EE）和身体功能障碍的生物标志物。 重量/组成作为偶发临床疾病的早期指标。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 有ALS遗传风险的个体中的靶点。我假设1）血浆脂质介质（脂质体）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 C9 orf 72 + ALS、症状前C9 orf 72突变携带者之间的体重/组成和EE不同 （C9 orf 72 + Pre-ALS）参与者和对照者3）某些代谢谱将预测C9 orf 72 + Pre-ALS患者的症状发作。 C9 orf 72+前ALS参与者。在这项研究中，我将1）研究ALS的血浆脂质体分布 和PLS受试者以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 C9 orf 72 + ALS和Pre-ALS中的体重/组成和EE，以测量能量代谢的变化 在疾病之前和整个疾病过程中，以及3）跟踪C9 orf 72 + Pre-ALS参与者的队列 每年跟踪ALS症状和体征的出现，以确定某些代谢特征是否预测 在这个遗传易感人群中出现症状。该项目的成功完成将为 关键数据1）建立脂质组谱作为ALS和PLS的诊断生物标志物，和2）提供 为C9 orf 72 + Pre-ALS个体的前瞻性队列研究奠定了基础，以确定脂质组特征是否 代谢指标（体成分，EE）可以作为表型的前兆标志物 从无症状到有症状的ALS的转变。K23将提供必要的支持， 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 临床应用的先进统计技术。我将充分利用我在 K23领导一项对ALS前参与者的纵向队列研究，以确定 代谢变化和ALS的临床表现。我的首要目标是找出早期诊断 生物标志物和治疗靶点，用于开发有效的治疗以预防或延迟 ALS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.