MINORITY PREDOCTORAL FELLOWSHIP PROGRAM

描述（由申请人提供）：帕金森病（PD）是最常见的神经退行性运动障碍，但目前的治疗方法不足以对抗症状的恶化，也无法逆转或阻止神经元细胞的死亡。最近，编码DJ-1基因的突变被认为与早发性常染色体隐性帕金森病有关。多种证据表明，DJ-1在细胞防御氧化应激中的作用，但其作用机制尚不清楚。我们和其他人发现DJ-1的一部分定位于线粒体，有趣的是，线粒体缺陷先前与帕金森病有关。此外，线粒体被认为是细胞氧化应激的主要来源，在细胞凋亡的开始和执行中也起着核心作用。该项目将试图表征DJ-1的亚细胞定位，确定DJ-1的线粒体结合伙伴，并验证DJ-1是线粒体依赖性凋亡的关键调节因子的假设。了解DJ-1在线粒体中的作用将增强我们对帕金森病发病机制的理解，并有可能确定关键的分子途径，可能为治疗干预提供新的靶点。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the most common neurodegenerative movement disorder, yet current treatments are insufficient to battle worsening symptoms and do little to reverse or halt neuronal cell death. Recently, mutations in the gene encoding DJ-1 have been implicated in an early-onset autosomal recessive form of PD. Multiple lines of evidence have suggested a role for DJ-1 in the cellular defense against oxidative stress, yet the mechanism of action remains unknown. We and others have found that a portion of DJ-1 localizes to the mitochondria and interestingly, mitochondrial deficits have previously been implicated in PD. In addition, mitochondria are known to be the major source of cellular oxidative stress and are also known to play a central role in initiation and execution of apoptosis. This project will seek to characterize the subcellular localization of DJ-1, to identify DJ-1 mitochondrial-binding partners, and to test the hypothesis that DJ-1 is a critical regulator of mitochondria-dependent apoptosis. Understanding the role of DJ-1 within the mitochondria will enhance our understanding of PD pathogenesis and could potentially identify critical molecular pathways, possibly providing new targets for therapeutic intervention.