InvestigatorColin Combs, Ph.D.

Location:  Department of Biomedical Sciences, University of North Dakota

Project Title:  Neuroinflammatory mechanisms of neurodegeneration

Description:  One of our research goals is to determine the mechanisms by which inflammatory activation of brain glial cells contributes to neurodegeneration.  Currently, our main interest is the process by which a specific type of glia, microglia, contribute to the pathophysiology of Alzheimer's disease (AD).  AD is a neurodegenerative disorder characterized by progressive dementia and an accumulation of extracellular senile plaques and intracellular neurofibrillary tangles in the brain.  In addition, diseased brains exhibit a profoundly increased microglial and astrocyte activation phenotype.  One prevailing theory is that this "gliosis" contributes to the neuron loss that is observed during disease.
Microglia are the resident immune effector cells of the brain and their activation state can likely contribute to both degeneration and regeneration.  This dichotomy provides the opportunity to modulate their phenotype to promote their regenerative function while limiting their degenerative behavior.  For example, it is now becoming clearer that many of the neurodegenerative diseases that afflict our brains result, in part, from aberrant microglial responses.  In addition to AD, Parkinson's disease, amyotropic lateral sclerosis, and multiple sclerosis are other examples of chronic nervous system diseases in which microglial hyper-reactivity likely contributes to the cell death that occurs.  We are working to understand specifically what goes wrong with the microglia in these conditions.  Once we identify the nature of the pathologic response, we work to stop or reverse it in an effort to promote cell survival in the brain.  This approach allows us to identify and propose novel therapeutic agents for treating these diseases.  We routinely use in vitro primary cell culture models of disease to first define our molecular targets for therapeutic intervention.  Next, we verify the efficacy of our approach through in vivo whole animal rodent models of disease.  Currently we are pursuing ongoing projects related to AD, Parkinson's disease, cerebrovascular disease, and multiple sclerosis.