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.

Public Health Relevance

A specific type of neurodegenerative disease termed neuroaxonal dystrophy (NAD) is associated with abnormalities in vitamin E transport or metabolism. Through a comparative approach using a laboratory model of vitamin-E associated neurodegeneration in mice and a naturally occurring inherited disease in horses, discovery of the molecular mechanisms involved in vitamin E-associated NAD will identify genes and pathways to target in both diagnostic and therapeutic aspects of NAD. Increased insight into the role of vitamin E in NAD in comparative animal species will contribute to our understanding of the interplay between vitamin E and neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01OD015134-05
Application #
9281058
Study Section
Special Emphasis Panel (ZTR1-CM-6 (01))
Program Officer
Fuchs, Bruce
Project Start
2013-07-22
Project End
2018-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
5
Fiscal Year
2017
Total Cost
$101,354
Indirect Cost
$7,508
Name
University of California Davis
Department
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Finno, Carrie J; Estell, Krista E; Winfield, Laramie et al. (2018) Lipid peroxidation biomarkers for evaluating oxidative stress in equine neuroaxonal dystrophy. J Vet Intern Med 32:1740-1747
Finno, Carrie J; Gianino, Giuliana; Perumbakkam, Sudeep et al. (2018) A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses. Skelet Muscle 8:7
Scott, E Y; Woolard, K D; Finno, C J et al. (2018) Variation in MUTYH expression in Arabian horses with Cerebellar Abiotrophy. Brain Res 1678:330-336
Kalbfleisch, Theodore S; Rice, Edward S; DePriest Jr, Michael S et al. (2018) Improved reference genome for the domestic horse increases assembly contiguity and composition. Commun Biol 1:197
Finno, Carrie J; Bordbari, Matthew H; Gianino, Giuliana et al. (2018) An innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in Ttpa-null mice. Free Radic Biol Med 120:289-302
Burns, E N; Bordbari, M H; Mienaltowski, M J et al. (2018) Generation of an equine biobank to be used for Functional Annotation of Animal Genomes project. Anim Genet 49:564-570
Scott, Erica Yuki; Woolard, Kevin Douglas; Finno, Carrie J et al. (2018) Cerebellar Abiotrophy Across Domestic Species. Cerebellum 17:372-379
Valberg, Stephanie J; Henry, Marisa L; Perumbakkam, Sudeep et al. (2018) An E321G MYH1 mutation is strongly associated with nonexertional rhabdomyolysis in Quarter Horses. J Vet Intern Med 32:1718-1725
Estell, Krista; Spriet, Mathieu; Phillips, Kathryn L et al. (2018) Current dorsal myelographic column and dural diameter reduction rules do not apply at the cervicothoracic junction in horses. Vet Radiol Ultrasound 59:662-666
Brown, J C; Valberg, S J; Hogg, M et al. (2017) Effects of feeding two RRR-?-tocopherol formulations on serum, cerebrospinal fluid and muscle ?-tocopherol concentrations in horses with subclinical vitamin E deficiency. Equine Vet J 49:753-758

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