Multiple sclerosis (MS) is the most devastating neurological disease in young adults, affecting more than 2.5 million people worldwide. Current therapies to treat MS and other demyelinating diseases are primarily focused on control of the immune component and inflammation in the disease. These treatments are not directed at repairing the damage in the central nervous system through remyelination. Studies are currently underway in many laboratories to identify small molecules that will enhance remyelination. Some of these studies are focused on specific identifiable pathways, while others are essentially "black box" screens, for which the molecular target may not be known, but the phenotypic target, myelination, can be identified. Once such lead molecules are identified, their optimization is needed. Optimization includes medicinal chemistry, but the screening of derivatives of lead compounds can be a lengthy and possibly unsuccessful process, if the in vivo impact of these compounds is not established at an early stage. The current project focuses on developing a new in vivo screen for drugs that will enhance myelination. The zebrafish model is becoming an important in vivo screen for drugs. Myelination occurs in the zebrafish over a rapid time frame, with significant myelination of the spinal cord by seven days post fertilization. Given the transparency of the embryo, fluorescent protein tags are an easy screen for increases in myelination. In order to accomplish our main goal, we will develop a new transgenic zebrafish line that will be an excellent readout of myelination per se. We will drive fluorescent protein reporter expression with the Protein zero (P0) promoter, which in the zebrafish is expressed early and strongly in oligodendrocytes and only much later in the peripheral nervous system. This will specifically mark mature oligodendrocytes as well as their myelin sheaths, allowing fluorescent protein imaging as a rapid readout of drug efficacy. Using an in vivo approach will allow us to screen out numerous drugs for toxicity or other negative impacts. We will optimize imaging techniques as complementary readouts of myelination per se, studying in vivo time lapse imaging to establish optimal time frames and regional assessment of drugs enhancing myelination.

Public Health Relevance

Multiple sclerosis (MS) is the most devastating neurological disease in young adults, affecting more than 2.5 million people worldwide. While therapies are being tested that reduce the immune/inflammatory component of the disease, repair and remyelination of the damaged tissue is still poorly treated. The current project focuses on developing zebrafish as a screening tool to optimize identifying drugs that will enhance myelination. The benefits of this system are that drugs can be screened in large numbers through a rapid in vivo system that tests efficacy and toxicity within five days, allowing rapid identification of optimized remyelination drugs for further preclinical testing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS078386-01
Application #
8287502
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Utz, Ursula
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$188,963
Indirect Cost
$63,963
Name
University of Colorado Denver
Department
Biology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045