Microglia phenotype and function is highly plastic and dependent on both their current environmental cues and their recent activation/differentiation history.  We have begun to define stable microglial heterogeneity in the healthy adult CNS using open and closed gene expression profiling methodologies, coupled with in situ hybridization analysis, real-time PCR analysis and ex vivo assays of immune function.  Strikingly, we find that microglial phenotype and function is age dependent. Neonatal microglia differ from juvenile microglia which differ from elderly microglia. 

These age and region-specific phenotypic differences likely reflect the health, activity and metabolic needs of the local neuronal environment.  By defining these differences in molecular terms, we can begin to define age and region specific susceptibility to neuroinflammatory insults and perhaps identify directed points of therapeutic intervention.

Molecular Tipping Points between Neuroprotective and Neurodestructive Effector Functions:

We are currently focusing on three interdependent immune modulatory tipping points:

1. 1)TREM/TLT family of immune modulatory receptors
   

2. 2)Tmem176b: an intracellular modulator of microglial function
   

3. 3)Polyamines as regulators of CNS inflammatory responses
   

Tools:

We modulate TREM, TLT and Tmem176b expression using

1. 1)Lentiviral vectors (overexpression/Knock-down)
   

2. 2)Irradiation Chimeric Models for the differential expression of overexpression/knock-down vectors in the peripheral immune system versus the CNS
   

We quantify the regulatory function of these molecules by contrasting the effects of overexpression and knock-down in

1. a)acute, remitting and chronic in vivo models of CNS neurodegeneration or autoimmunity
   

2. b)in vitro co-culture systems