PKAN pathogenesis and treatment

PKAN发病机制及治疗

基本信息

批准号：
9788120
负责人：
SUSAN J HAYFLICK
金额：
$ 33.69万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788120
关键词：
4&apos -phosphopantetheine Acyl Carrier Protein Adult Age Biochemical Reaction Biogenesis Biological Markers Blindness Brain Brain region Carrier Proteins Cell Line Cell physiology Cells Cessation of life Child Coenzyme A Complex Consumption Data Defect Development Disease Disease model Dopamine Dystonia Elements Fatty Acids Functional disorder Gender Gene Expression Genes Genetic Genetic Diseases Goals Hallervorden-Spatz Syndrome Hereditary Disease Homeostasis Human Intervention Trial Iron Isoenzymes Knockout Mice Knowledge Leukocytes Link Mammals Mediating Mendelian disorder Metabolic Metabolism Mitochondria Mitochondrial Proteins Modeling Molecular Molecular Profiling Mus Mutant Strains Mice Nerve Degeneration Neurodegenerative Disorders Oral Oxidative Phosphorylation Pain Pantothenate kinase Parkinsonian Disorders Pathogenesis Pathway interactions Phenotype Process Prosthesis Reaction Research Resources Role Rotenone Source Sulfur Surrogate Markers System Testing Therapeutic Translating Treatment Efficacy brain abnormalities burden of illness dopaminergic neuron gene repression improved insight mouse model neurotransmission novel strategies therapeutic candidate therapeutic evaluation tool

项目摘要

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.

项目概要/摘要单基因疾病为常见疾病的机制提供了宝贵的见解，并具有高度代表性用于开发合理疗法的易于处理的系统。 PKAN（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，导致肌张力障碍、帕金森症、儿童和成人失明和早逝。目前尚无缓解疾病的治疗方法。我们的长期目标是阐明这种致命疾病的发病机制并开发治疗方法。 PKAN 是辅酶 A (CoA) 合成的先天性错误，可导致脑铁引起的神经变性积累。尽管脑铁积累是 PKAN 的一个标志，但 CoA 缺陷之间的联系代谢、铁稳态失调和神经退行性疾病仍不清楚。缺乏稳健的 PKAN 哺乳动物疾病模型限制了研究进展，并且仍然代表着该领域的关键研究资源。使用小鼠敲除 Pank2 和新的分离方法与疾病保护的大脑区域相比，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 CoA、铁和多巴胺代谢紊乱的标记氧化磷酸化仅在疾病易感区域发生。我们建议调查这个强大的模型的目标是描绘 PKAN 的分子发病机制，以证明候选药物的功效治疗，并发现可转化用于人体干预试验的生物标志物。