What do microglia do? Microglia are myeloid-derived residents of the brain that can mount immune responses to pathologic events in the brain and periphery. Recently, we and others have identified roles for microglia in physiologic processes of the CNS, such as in synapse elimination during development. However, the inability to reliably distinguish microglia from closely related myeloid cells confounds many reports of microglial function in health and disease. Therefore, we sought out a protein marker that would allow the reliable identification, targeting, and characterization of microglia. I identified TM119 as such a marker by a screen based on our extensive cell specific gene expression arrays and confirmed with in situ hybridization. In this application, I will test the hypothesis that a subset of microglia are "alternatively activated", meaning that upon activation they limit inflammation and promote tissue repair, and that these microglia limit CNS injury. I wil then test if selective loss of microglia hinders CNS repair. In the first aim, I will characterize TM119 expression throughout development and test a TM119-based tool, a TM119/CreERT2 BAC transgenic mouse, to genetically target microglia. In the second aim, I will use this mouse to specifically prevent alternative activation of microglia and examine the effect of this on injur severity following crush injury to the optic nerve. In the final aim, I will ablate microglia using Diphtheria toxin targeted to microglia with the TM119/CreERT2 mouse to determine if they are required for CNS repair and neuroprotection. These studies have the potential to dissect and understand, for the first time, the specific contribution of microglia to CNS injury and repair.

Public Health Relevance

This proposal aims to study the mysterious immune cells of the CNS-microglia-and their role in injury response and repair, which will provide insight into mechanisms of neurological disease and potential therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS078813-02
Application #
8468585
Study Section
NST-2 Subcommittee (NST)
Program Officer
Jakeman, Lyn B
Project Start
2012-04-26
Project End
2016-04-25
Budget Start
2013-04-26
Budget End
2014-04-25
Support Year
2
Fiscal Year
2013
Total Cost
$34,051
Indirect Cost
Name
Stanford University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305