Glia are non-neuronal cells with diverse functions that range from forming the myelin sheath to defending the brain against infection. A major goal of our research is to use the powerful experimental advantages of zebrafish to discover new genes that are essential for the development and function of two classes of glia in the CNS, oligodendrocytes and microglia. Oligodendrocytes form myelin on axons in the CNS. After an oligodendrocyte begins to myelinate axons, it has only a short developmental window (or ?critical period?) to extend new myelinating processes. Using genetic and cellular approaches in zebrafish, we have identified a number of positive and negative regulators of myelination. One of our goals is to determine how these factors control myelination during development, neural plasticity, and remyelination. In addition, we will investigate the molecular basis of the critical period. Microglia are highly motile, phagocytic glial cells in the CNS that destroy pathogens and clear debris such as apoptotic cells and damaged axons. Despite the importance of microglia in CNS health and disease, many critical questions remain to be addressed about these cells. We have conducted zebrafish mutational screens to discover essential microglial genes, and we are characterizing their functions using in vivo imaging and other approaches. The mechanistic insight gained from these studies will advance our fundamental understanding of the central nervous system, illuminate the pathways that are disrupted in diseases of the brain, and suggest avenues toward therapies for neurological disorders.

Public Health Relevance

Oligodendrocytes and microglia are two types of glial cells with critical functions in the brain. Despite their important roles in health and disease, many questions remain unanswered about the genetic mechanisms that control the development and function of these cells. The goal of this project is to use the powerful genetic and cellular approaches in the zebrafish model system to discover new genes with essential functions in oligodendrocytes and microglia. The mechanistic insight gained from these studies will advance our fundamental understanding of the central nervous system, illuminate the pathways that are disrupted in diseases of the brain, and suggest avenues toward therapies for neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Unknown (R35)
Project #
1R35NS111584-01
Application #
9744431
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Morris, Jill A
Project Start
2019-05-01
Project End
2027-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305