The molecular effect of early psychosine accumulation in Krabbe disease has not been studied in primary central nervous system (CNS) progenitor cell populations, specifically those of the oligodendroglial lineage responsible for proper myelination. By the time early onset Krabbe disease patients have presented with neurological symptoms, damage to the CNS may be irreparable due to early accumulation of abnormal levels of psychosine and its effect on vulnerable progenitor populations during critical developmental periods. Preliminary data suggests that physiologically relevant concentrations of psychosine are activating the previously described [13] redox/Fyn/c-Cbl pathway in primary oligodendrocyte/type-2 astrocyte progenitor cells (O-2A/OPCs). This pathway plays an important role in normal O-2A/OPC proliferation and migration. Further investigations on this pathway will better define cellular and molecular mechanisms of psychosine toxicity. Moreover, FDA-approved drugs in the NINDS II library will be screened to identify those that either ameliorate or exacerbate the toxic effects of psychosine. Rapid in vitro screening will be conducted using an automated adherent cell cytometry system. Candidate drugs will be further tested in vivo in the early onset Krabbe disease mouse model, the twitcher mouse. Developmental effects will be identified through immunohistochemical staining of brain and spinal cord sections and Western blot analysis. Behavioral and motor function tests, lifespan and symptom severity will be conducted as functional readouts of drug treatment. The goal is to protect early CNS development from effects of endogenous psychosine accumulation in early onset Krabbe patients through drug treatment intervention, ultimately to enable increased efficacy when used in combination with genetic and enzymatic replacement therapies.

Public Health Relevance

Krabbe Disease is a debilitating genetic disorder of the nervous system that affects 1 in 100,000 live births in the United States (however the carrier rate for common mutations is estimated at 1 in 125 individuals) and results in severe neurological degeneration, demyelination, and death. At present there is no cure, and current therapeutic interventions have little beneficial effect in patients that have the more severe early onset (infantile) form of the disease. My research aims to identify abnormalities in early nervous system development due to alterations in normal progenitor cell biology and to screen FDA-approved drugs that ameliorate or exacerbate these effects to contribute to a multi-therapeutic approach that affords increased length and quality of life to patients that currently have no efficacious treatment options.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS078911-03
Application #
8643304
Study Section
Special Emphasis Panel (ZRG1-F03A-N (20))
Program Officer
Morris, Jill A
Project Start
2012-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$36,276
Indirect Cost
Name
University of Rochester
Department
Genetics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627