Metabolic Profiling of OXPHOS Dysfunction

说明（申请人提供）：氧化磷酸化（OXPHOS）是指细胞产生ATP的核心生化途径。在过去的20年里，它已经变得非常明显，无论是先天性的代谢缺陷，以及共同的，退行性疾病源于OXPHOS功能障碍。单一途径中的缺陷如何传递到其他生化途径，从而引起如此多的不同综合征和疾病，目前尚不清楚。此外，诊断线粒体代谢的先天性缺陷是非常具有挑战性的。我们假设，各种生化途径是有条件地激活响应OXPHOS功能障碍，使细胞适应疾病状态。使用新兴的“代谢组学”技术，我们建议系统地确定这种耦合的生化途径。我们将利用培养的细胞以及已知OXPHOS遗传疾病的人，并分析细胞和血浆代谢产物，以确定细胞代谢如何适应OXPHOS缺陷。我们发现的生物化学网络可能会揭示疾病的发病机制，可能是治疗的目标，并可能立即提供OXPHOS疾病的生物标志物。目前的研究应该为更好地了解OXPHOS在一些常见人类疾病中的作用奠定基础。公共卫生相关性：我们最近发现了一个关键的细胞通路，该通路在糖尿病等代谢疾病中发生改变。使用新的测量技术，我们希望更好地了解这些途径的改变如何在细胞和人类中引起疾病。如果成功的话，我们的研究可以帮助诊断代谢疾病，也有助于激励新疗法的设计。

DESCRIPTIONS (provided by applicant): Oxidative phosphorylation (OXPHOS) refers to the cell's core biochemical pathway for generating ATP. During the past 20 years, it's become abundantly evident that both inborn errors of metabolism as well as common, degenerative diseases stem from OXPHOS dysfunction. How defects in a single pathway transmit to other biochemical pathways to give rise to so many different syndromes and diseases is not clear. Moreover, diagnosing the inborn errors of mitochondrial metabolism is incredibly challenging. We hypothesize that a variety of biochemical pathways are conditionally activated in response to OXPHOS dysfunction, to permit the cell to adapt to the disease state. Using emerging "metabolomics" technologies, we propose to systematically identify such coupled biochemical pathways. We will utilize cells in culture as well as humans with known OXPHOS genetic diseases and profile cellular and plasma metabolites to determine how cellular metabolism adapts to defects in OXPHOS. The biochemical networks we uncover may shed insights into disease pathogenesis, may be targeted for therapy, and may immediately provide a biomarker for OXPHOS disease. The current study should lay the foundation for better understanding the role of OXPHOS in a number of common human diseases. PUBLIC HEALTH RELEVANCE: We have recently discovered a key cellular pathway that is altered in metabolic disorders such as diabetes. Using novel measurement technologies, we hope to better understand how alterations in these pathways give rise to disease in cells as well as in humans. If successful, our research could assist in the diagnosis of metabolic diseases, and also help motivate the design of novel therapies.