Through a career development plan which includes structured didactics, multidisciplinary mentoring and innovative research experience, the applicant will acquire skills and knowledge required as an independent investigator. The applicant will gain the expertise in proteomics and glial cell biology, as applicable to a career as a neuroscientist. Together with the proposed research experience, this will position her as a future leader in the field of heritable white matter disorders. The research plan aims to identify pathophysiological mechanisms and explore therapeutic targets in Vanishing White Matter (VWM) disease, a leukodystrophy caused by mutations in the eukaryotic translation initiation factor 2B (elF2B) gene. New preliminary data indicate that elF2B mutated cells display an abnormal accumulation of proteins within the endoplasmic reticulum (ER) as a response to stress. We hypothesize that abnormal protein trafficking, as a result of abnormally regulated ER stress, occurs in VWM, and is largely responsible for the phenotype of progressive myelin destruction in this disorder. The proposed aims are to: 1) define protein trafficking alterations in glial cells affected by elF2B mutations or RNA interference using a comparative proteomics approach (SILAC) combined with mass spectrometry to identify proteins with abnormal ER storage and secretion as a function of a number of chemical and physical stressors 2) determine the effect of chaperones on protein trafficking in elF2B mutated CMS cells by monitoring the effect of these candidate therapeutic molecules on the proteins identified in Aim 1. We will initially perform these studies on elF2B knockdown oligodendrocytes, and subsequently validate this paradigm on CNS cells obtained from a mouse model of VWM disease. The therapeutic effect of 4-phenylbutyrate (chemical chaperone), Salubrinal (translation factor inhibitor), and a select group of molecules identified by high throughput screening in elF2B mutated yeast, will be tested for ameliorating effect on stress response in VWM models. Agents (drugs) identified as effective in vitro will be tested in the mouse model and ultimately in patients affected by VWM as a long-term goal of this research. This research goal is consistent with the career goal of the applicant to improve understanding and treatment of patients with leukodystrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS060695-02
Application #
7770903
Study Section
NST-2 Subcommittee (NST)
Program Officer
Tagle, Danilo A
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$126,198
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
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Vanderver, Adeline; Simons, Cas; Helman, Guy et al. (2016) Whole exome sequencing in patients with white matter abnormalities. Ann Neurol 79:1031-1037
Helman, Guy; Van Haren, Keith; Bonkowsky, Joshua L et al. (2015) Disease specific therapies in leukodystrophies and leukoencephalopathies. Mol Genet Metab 114:527-36
Helman, Guy; Van Haren, Keith; Escolar, Maria L et al. (2015) Emerging treatments for pediatric leukodystrophies. Pediatr Clin North Am 62:649-66
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Van Haren, Keith; Bonkowsky, Joshua L; Bernard, Genevieve et al. (2015) Consensus statement on preventive and symptomatic care of leukodystrophy patients. Mol Genet Metab 114:516-26
Vanderver, Adeline; Prust, Morgan; Tonduti, Davide et al. (2015) Case definition and classification of leukodystrophies and leukoencephalopathies. Mol Genet Metab 114:494-500
Vanderver, Adeline; Simons, Cas; Schmidt, Johanna L et al. (2014) Identification of a novel de novo p.Phe932Ile KCNT1 mutation in a patient with leukoencephalopathy and severe epilepsy. Pediatr Neurol 50:112-4
Tonduti, Davide; Vanderver, Adeline; Berardinelli, Angela et al. (2013) MCT8 deficiency: extrapyramidal symptoms and delayed myelination as prominent features. J Child Neurol 28:795-800
Simons, Cas; Wolf, Nicole I; McNeil, Nathan et al. (2013) A de novo mutation in the ?-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum. Am J Hum Genet 92:767-73

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