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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
NST-2 Subcommittee (NST)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Research Institute
United States
Zip Code
Adang, Laura A; Sherbini, Omar; Ball, Laura et al. (2017) Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies. Mol Genet Metab 122:18-32
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
Parikh, Sumit; Bernard, Geneviève; Leventer, Richard J et al. (2015) A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies. Mol Genet Metab 114:501-515
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
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
Kevelam, Sietske H; Rodenburg, Richard J; Wolf, Nicole I et al. (2013) NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern. Neurology 80:1577-83

Showing the most recent 10 out of 34 publications