Robert J. McKeon, PhD

Associate Professor

Department of Cell Biology

Office: 405M Whitehead Research Bldg

Phone: 404 727-6956

Email: rmckeon@emory.edu

Office Location:

Mailing Address:

Emory University - Department of Cell Biology

615 Michael St, 1941/001/1AF

Atlanta, GA 30322

Research Focus

Research in my lab is focused on examining the cellular response to central nervous system (CNS) injury. After damage to the CNS, injured axons fail to regenerate due to the formation of a non-neuronal glial barrier comprised predominantly of reactive astrocytes. The extracellular matrix of this astrogliotic tissue contains axon growth inhibitory chondroitin sulfate proteoglycans (CS-PGs) that are produced by reactive astrocytes. We have recently determined that two CS-PGs, neurocan and phosphacan, are localized to glial scars and that the astrocytic expression of neurocan is specifically upregulated by the injury-induced cytokine transforming growth factor-ß (TGF-ß). Immunoneutralization of TGF–ß decreases neurocan expression by cultured astrocytes and enhances process outgrowth from hippocampal neurons. Importantly, new preliminary data demonstrates that in vivo immunoneutralization of TGF-ß enhances axonal regeneration in a model of indirect spinal cord injury. The ongoing goal of this project is to elucidate the regulation of astrocytic CS-PGs by examining TGF-ß mediated CS-PG gene expression. Our long-term goal continues to be directed towards developing strategies to block injury-induced expression of CS-PGs in hopes of promoting axonal regeneration after CNS injury.

Although reactive astrocytes inhibit axonal regeneration, their functions are quite diverse and, in some cases, neuroprotective. For example, reactive astrocytes secrete neurotrophic factors and re-establish ionic homeostasis. Astrocytes also remove the excitatory neurotransmitter glutamate from the extracellular space, thereby protecting neurons from excitotoxic-mediated cell death. Glutamate uptake, along with many other functions of reactive astrocytes, is energy dependent. In collaboration with the laboratory of Dr. Charles Buck, Dept. of Physiology, we have discovered that the expression of the adenine nucleotide translocator-1 (ANT1) is specifically upregulated in reactive astrocytes. ANT1 is an inner mitochondrial membrane protein that exchanges cytosolic ADP for mitochondrial ATP. These data provide the first evidence of an increased demand for energy placed on astrocytes under stress. The functional significance of ANT1 is demonstrated by a dramatic reduction in glutamate uptake by ANT1 null mutant astrocytes compared to genetically matched controls. Consistent with this finding, ANT1 null mutant astrocytes demonstrate decreased ATP levels. We are currently examining the significance of astrocytic ANT1 expression in vivo by determining neuronal survival in ANT1 null mutant versus genetically matched control mice after CNS injury. With the studies described above, these experiments will provide important mechanistic insight into the function of reactive astrocytes by examining the requirement for mitochondrial energy during biologically significant processes ranging from neuronal survival to axonal regenerative failure.

Publications