Mitochondrial Disease: Neuronal Defects in Cell Culture

描述（由申请人提供）：线粒体基因组（mtDNA）缺陷是临床上重要的神经系统疾病的重要原因。尽管这种认识和线粒体基因组的小尺寸，潜在的疾病机制仍然不确定。 因此，尽管诊断是可能的，但临床医生很难为患者提供超过有限的帮助。该项目旨在通过首次对神经元自身内发生的近端缺陷进行彻底检查，阐明mtDNA突变与所导致的神经系统疾病之间的联系。这将通过在人、成人来源的胚胎癌细胞（不是胚胎干细胞）中产生线粒体胞质杂交体来完成，从而在人来源的培养的神经元中建立线粒体疾病的模型系统。神经元的细胞缺陷将通过分析神经元的发育、神经递质表达、电生理学、细胞死亡敏感性和生物能量学来表征。希望在细胞水平上的特定缺陷的知识将允许更好地靶向治疗线粒体呼吸链疾病。

DESCRIPTION (provided by applicant): Defects in the mitochondrial genome (mtDNA) are a significant cause of clinically important neurological disease. Despite this recognition and the small size of the mitochondrial genome, the underlying disease mechanisms remain uncertain. Thus, though diagnosis is possible, it is difficult for clinicians to offer more than limited help to patients. This project aims to elucidate the connection between a mtDNA mutation and the resulting neurological disorder by undertaking, for the first time, a thorough examination of the proximal defects occurring within the neurons themselves. This will be done by creating transmitochondrial cybrids in human, adult-derived embryonal carcinoma cells (not embryonic stem cells) and thereby establishing a model system of mitochondrial disorders in human-derived, cultured neurons. The cellular defects of the neurons will be characterized by analyzing the development, neurotransmitter expression, electrophysiology, cell death sensitivity, and bioenergetics of the neurons. Hopefully, the knowledge of the specific defects at the cellular level will allow better targeting for therapy of disorders of the mitochondrial respiratory chain.