PKAN pathogenesis and treatment

项目总结/摘要 单基因疾病为常见疾病的机制提供了有价值的见解，并代表了高度 开发合理疗法的易处理系统。泛酸激酶相关 神经变性）是一种严重致残和痛苦的遗传性疾病，引起肌张力障碍，帕金森症， 儿童和成人的失明和早逝。目前还没有疾病修饰治疗。我们 长期目标是阐明发病机理并开发这种致命疾病的治疗方法。 PKAN是辅酶A（CoA）合成的先天性错误，导致脑铁神经变性 积累虽然脑铁积累是PKAN的一个标志，但缺陷CoA与PKAN之间的联系可能是一个潜在的联系。 铁代谢、铁稳态异常和神经变性仍不清楚。 缺乏一个强大的哺乳动物疾病模型的PKAN限制了研究进展，仍然代表了一个新的研究领域。 该领域的关键研究资源。使用小鼠敲除Pank 2和一种新的分离方法 我们发现了一组与疾病相关的大脑区域， 异常这种分子“特征”包括辅酶A、铁和多巴胺代谢紊乱的标志物 氧化磷酸化只在易患病的区域。我们建议调查这个强大的 该模型的目标是描述PKAN的分子发病机制，以证明候选药物的有效性， 治疗，并发现可用于人类干预试验的生物标志物。

PROJECT SUMMARY/ABSTRACT Single gene disorders provide valuable insights into mechanisms of common diseases and represent highly tractable systems for developing rational therapeutics. PKAN (pantothenate kinase-associated neurodegeneration) is a profoundly disabling and painful genetic disorder causing dystonia, parkinsonism, blindness and early death in children and adults. Currently there are no disease-modifying treatments. Our long-term goals are to elucidate pathogenesis and develop a treatment for this lethal disease. PKAN is an inborn error of coenzyme A (CoA) synthesis that results in neurodegeneration with brain iron accumulation. Though brain iron accumulation is a hallmark of PKAN, the link between defective CoA metabolism, iron dyshomeostasis, and neurodegeneration has remained unclear. The lack of a robust mammalian disease model of PKAN has limited research progress and still represents a critical research resource for the field. Using a mouse knock-out of Pank2 and a new approach to separating disease-vulnerable from disease-protected brain regions, we have discovered a set of disease-relevant brain abnormalities. This molecular `signature' includes markers of perturbed CoA, iron, and dopamine metabolism and oxidative phosphorylation only in the disease-vulnerable regions. We propose to investigate this powerful model with the goals to delineate the molecular pathogenesis of PKAN, to demonstrate efficacy of a candidate therapeutic, and to discover biomarkers that can be translated for use in human interventional trials.