Grant Abstract: Molecular pathogenesis of alpha-tocopherol associated neuroaxonal dystrophy in an

Grant Number: 5K01OD015134-04
PI Name: Finno
Project Title: Molecular pathogenesis of alpha-tocopherol associated neuroaxonal dystrophy in an

Abstract: Validated biomarkers and suitable animal models are required to address the fundamental lack of research into the efficacy of nutraceuticals, a $250 billion dollar industry. Despite several decades of research, our understanding of the role that vitamin E, specifically a-tocopherol (a-TP), plays in health and disease remains quite limited. Most Americans get less than the recommended daily allowance of a-TP in their diets, however, beneficial effects of supplementation remain controversial. I propose to develop novel biomarkers that will be invaluable for investigating potential neuroprotective effects of a-TP supplementation by using our current murine and equine models of a-TP deficient neurodegenerative disease. Domestic animals develop neurodegenerative diseases that are impacted by tissue a-tocopherol levels and have striking histopathologic similarities to ataxia with vitamin E deficiency in humans, caused by genetic mutations in tocopherol (alpha) transfer protein, TTPA. A comparative medicine approach may be the key to unraveling the pathophysiologic basis for this a-TP deficient NAD. The long-term goal of my research is to employ a multidisciplinary translational approach to discover molecular mechanisms responsible for a-TP deficient neurodegeneration. The overall objective of this proposal is to define dysregulated pathways in two a- TP deficient animal models: spontaneous neuroaxonal dystrophy (NAD) in the horse and experimental Ttpanull mice. The central hypothesis is that the genetic mutations associated with equine NAD and Ttpa-null mice lead to increased oxidation of cholesterol, producing endogenous oxysterols, which activate liver X receptors (LXR). This proposal drives two specific aims targeted at uncovering the molecular mechanisms responsible for a-tocopherol deficient NAD and identifying potential biomarkers of a-TP efficacy. By defining the temporal gene expression patterns in the Ttpa-null mouse while simultaneously investigating the potential role of the biomarkers 7a-hydroxy-4-cholesten-3-one and oxysterols in naturally occurring equine NAD, novel comparative mechanisms will be identified and the role of vitamin E in neurodegeneration further defined. The administrative supplement to Dr. Carrie Finno’s K01 award would provide additional support towards her development as an early investigator DVM, PhD and strengthen her independent research program at the University of California, Davis. Dr. Finno has a keen interest in comparative genomics of neurodegenerative disorders and a desire to continue to advance her expertise in specialized pathologic techniques, transcriptomics and advanced biomedical research. The additional experience using mouse model will enhance Dr. Finno’s future research potential.

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