Molecular pathogenesis of alpha-tocopherol associated neuroaxonal dystrophy in an

描述（由申请人提供）：尽管经过几十年的研究，我们对维生素E，特别是α-生育酚在健康和疾病中的作用的理解仍然非常有限。α-生育酚在维持神经肌肉健康中的重要性首先通过发现编码α-生育酚转移蛋白（TTPA）的基因中的突变导致人类共济失调伴维生素E缺乏而阐明。影响α-生育酚转运和代谢的其他遗传性病症导致不同形式的神经轴突营养不良（NAD），其导致破坏性进行性神经变性疾病。然而，已经描述了与TTPA突变无关的类似共济失调伴维生素E缺乏的表型，并且关于α-生育酚相关NAD的分子发病机制仍有许多未知之处。 NAD的自然发生的家养动物模型受到组织α-生育酚水平的影响，并且与人类维生素E缺乏性共济失调具有惊人的组织病理学相似性。比较医学方法可能是解开这种α-生育酚相关NAD的病理生理基础的关键。我的研究的总体目标是采用多学科的比较方法来发现负责NAD的新机制。实验室小鼠模型和天然存在的大型动物模型存在α-生育酚相关的NAD。我的总体假设是，在NAD的小鼠和马模型中，α-T相关神经退行性变的机制是由参与α-T转运或代谢的基因突变与出生后发育期间饮食α-T浓度之间的时间相互作用引起的。此外，我假设这些形式的α-T相关神经变性的相似性将进一步说明与突触前功能相关的基因，即复合蛋白2和vamp 2的显着和时间进行性下调。这一提议推动了两个具体目标，旨在揭示负责α-生育酚相关NAD的分子机制。通过定义Ttpa缺陷小鼠的时间基因表达模式，同时揭示自然发生的马NAD模型中基因调控和失调的变化，将确定NAD的新的比较机制，并进一步确定维生素E在神经退行性变中的作用。 K 01奖将支持Carrie Finno博士作为博士后DVM，PhD的职业发展，并为她在学术环境中进行独立研究做好准备。Finno博士对神经退行性疾病的比较基因组学有浓厚的兴趣，并希望获得专业病理技术，转录组学和先进生物医学研究的专业知识。使用小鼠模型的经验将增强Finno博士未来的研究潜力。要求提供五年的辅导支持。

DESCRIPTION (provided by applicant): Despite several decades of research, our understanding of the role that vitamin E, specifically a-tocopherol, plays in health and disease remains quite limited. The importance of a-tocopherol in maintaining neuromuscular health was first elucidated by the discovery that mutations in the gene encoding a-tocopherol transfer protein (TTPA) cause ataxia with vitamin E deficiency in humans. Other inherited conditions that affect a-tocopherol transport and metabolism lead to distinct forms of neuroaxonal dystrophy (NAD), which result in devastating progressive neurodegenerative disease. However, phenotypes resembling ataxia with vitamin E deficiency have been described that are not associated with mutations of TTPA, and much remains unknown about the molecular pathogenesis of a-tocopherol-associated NAD. Naturally occurring domestic animal models of NAD are impacted by tissue a-tocopherol levels and have striking histopathologic similarities to ataxia with vitamin E deficiency in humans. A comparative medicine approach may be the key to unraveling the pathophysiologic basis for this a-tocopherol-associated NAD. The overall goal of my research is to employ a multi-disciplinary comparative approach to discover novel mechanisms responsible for NAD. A laboratory mouse model and a naturally occurring large animal model exist for alpha-tocopherol associated NAD. My overall hypothesis is that the mechanism of alpha-T-associated neurodegeneration in murine and equine models of NAD arises from the temporal interaction between mutations in genes involved in alpha-T transport or metabolism and dietary alpha-T concentrations during post-natal development. Additionally, I hypothesize that the similarity in these forms of alpha-T-associated neurodegeneration will be further illustrated by a significant and temporally progressive downregulation of genes associated with presynaptic function, namely complexin 2 and vamp2. This proposal drives two specific aims targeted at uncovering the molecular mechanisms responsible for alpha-tocopherol associated NAD. By defining the temporal gene expression patterns in the Ttpa-deficient mouse while simultaneously uncovering variations of gene regulation and dysregulation in the naturally-occurring equine NAD model, novel comparative mechanisms for NAD will be identified and the role of vitamin E in neurodegeneration further defined. The K01 award would support Dr. Carrie Finno's career development as a postdoctoral DVM, PhD and prepare her for independent research in an academic environment. Dr. Finno has a keen interest in comparative genomics of neurodegenerative disorders and a desire to gain expertise in specialized pathologic techniques, transcriptomics and advanced biomedical research. Experience using mouse model will enhance Dr. Finno's future research potential. Five years of mentored support is requested.