Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS and the major cause of non-traumatic neurological disability in young adults in North America and Europe. The best described and most extensive repair that occurs in the adult human brain is the production of new oligodendrocytes that remyelinate axons in MS lesions. Although this repair can be extensive, most lesions in chronic MS patients are not remyelinated. Remyelination requires the production of new oligodendrocytes from oligodendrocyte progenitor cells (OPC) that are present in adult brain, but dramatically reduced in chronically demyelinated MS lesions. Enhancement of endogenous OPC production is a viable therapeutic target in MS patients. The major goal of this competitive renewal is to obtain a better understanding of how multipotent CNS stem cells located in the subventricular zone (SVZ) of the telencephalon produce OPCs in response to demyelination. This renewal focuses on a SVZ cell, the betaT4 cell (identified by betaT4 tubulin antibodies) which is 1) abundant in developing human SVZ, 2) detected at low densities in mature brain, 3) increased in MS brains, and 4) displays many of the characteristics of a multipotential CNS stem cell in vitro. We hypothesize that betaT4 cells are a major source of OPCs during late fetal and early postnatal telencephalon development, remain at low levels in adult brain, and can produce new OPCs in response to demyelination. Our studies are divided into two Aims. The first will investigate the fate of betaT4 SVZ cells during rodent brain development and in response to demyelination. These studies will 1) directly follow progeny of betaT4 cells in vivo using Cre/lox P technology, 2) further characterize molecules expressed by betaT4 cells using a genomic approach, and 3) investigate molecules that affect betaT4 cell development in neurospheres assays.
The second Aim will continue to characterize betaT4 cells in MS lesions and developing human brains. Studies in humans are essential for accomplishing our long-term goals of understanding the role of betaT4 cells in repair of the adult brain. Collectively, these studies should identify therapeutic targets that enhance remyelination and reduce the progression of neurological disability in MS patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029818-18
Application #
7846171
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Utz, Ursula
Project Start
1991-09-30
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
18
Fiscal Year
2010
Total Cost
$334,168
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Power, C; Kong, P A; Trapp, B D (1996) Major histocompatibility complex class I expression in oligodendrocytes induces hypomyelination in transgenic mice. J Neurosci Res 44:165-73