Molecular pathogenesis of alpha-tocopherol associated neuroaxonal dystrophy in an

描述(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所起的作用的了解仍然相当有限。α-生育酚在维持神经肌肉健康方面的重要性首次被阐明，是因为发现编码α-生育酚转移蛋白(TTPA)的基因突变会导致人类维生素E缺乏性共济失调。其他影响生育酚运输和代谢的遗传性疾病会导致不同形式的神经轴索营养不良(NAD)，从而导致毁灭性的进行性神经退行性疾病。然而，类似于维生素E缺乏的共济失调的表型已被描述为与TTPA突变无关的表型，关于α-生育酚相关NAD的分子发病机制仍不清楚。 自然发生的家养NAD动物模型受组织α-生育酚水平的影响，与人类维生素E缺乏性共济失调具有显著的组织病理学相似之处。比较医学方法可能是解开这种α-生育酚相关NAD病理生理学基础的关键。我研究的总体目标是采用多学科比较的方法来发现导致NAD的新机制。与α-生育酚相关的NAD存在实验室小鼠模型和自然发生的大动物模型。我的总体假设是，NAD小鼠和马模型中与α-T相关的神经退行性变的机制源于参与α-T运输或代谢的基因突变与出生后发育期间饮食中的α-T浓度之间的时间相互作用。此外，我假设，与突触前功能相关的基因，即Complexin 2和vamp2的显著和时间渐进性下调，将进一步说明这些形式的阿尔法-T相关神经退行性变的相似性。这一提议推动了两个特定的目标，旨在揭示与α-生育酚相关的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，将识别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。 K01奖项将支持Carrie Finno博士作为博士后DVM和博士的职业发展，并为她在学术环境中进行独立研究做好准备。芬诺博士对神经退行性疾病的比较基因组学有着浓厚的兴趣，并渴望在专门的病理技术、转录学和高级生物医学研究方面获得专业知识。使用老鼠模型的经验将增强芬诺博士未来的研究潜力。需要五年的指导支持。

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.