Michael F. Miles, M.D., Ph.D. Professor 1217 East Marshall Street Hermes A. Kontos Medical Sciences Building P.O. Box 980599 Richmond, Virginia 23298-0599 Phone: (804) 827-4054 Fax: (804) 828-6432 E-mail: mfmiles@vcu.edu Publications: selected | PubMed Lab: http://www.brainchip.vcu.edu

Education: Northwestern University, Ph.D., 1982, Northwestern University, M.D., 1983

Research interests:

Use of functional genomics to understand the molecular mechanisms of experience-dependent plasticity occurring with drug abuse

Molecular mechanisms underlying sensitization to cocaine or ethanol

Sensitization refers to increased behavioral responses (e.g. locomotor activity) with repeated exposure to drugs of abuse. Sensitization increases the rewarding properties of addictive drugs. Expression profiling of basal gene expression in microdissected mouse brain regions during initiation of cocaine sensitization shows striking patterns of gene expression in the ventral tegmental area of DBA/2J mice. These expression patterns suggest functional changes that could contribute to increased dopamine release seen in nucleus accumbens with cocaine sensitization. Array studies, in combination with pharmacological, genetic and biochemical approaches, are currently being used to functionally link the regulation of specific genes to behavior of sensitization.

Molecular responses to acute ethanol exposure

There is a robust inverse relationship between acute ethanol sensitivity and long-term rates of ethanol self-administration in many different rodent models and in humans. We are studying patterns of gene regulation following acute ethanol exposure that correlate with long-term behavioral responses. Studies to date have identified a prominent role of prefrontal cortex in acute responses to ethanol. The gene expression patterns suggest several distinct targets of ethanol action. These include GABA-A receptors, a receptor known to be directly modulated by ethanol. Inbred lines, knockouts, gene delivery and pharmacological treatments are being used to correlate expression profiles with behavioral responses to acute ethanol. In addition, we are studying how “experience" with ethanol (sensitization, long-term drinking) alters the expression profiles seen with acute ethanol.

Molecular plasticity during acquisition of ethanol drinking behavior

In a collaborative project with Dr. Clyde Hodge, we are using DNA arrays to study molecular mechanisms of plasticity occurring in brain reward pathways as rats develop ethanol self-administration. We expect to implicate specific patterns of gene expression with the attainment or maintenance of ethanol self-administration. We also can identify subsets of genes serving tolerance or relapse. Initial array studies have identified striking changes in the expression of glutamate and GABA receptor subunits, both of which are known to be targets of acute ethanol action. Some changes identified in ethanol-drinking rats also have been seen in brain tissue from alcoholics. Further time course and pharmacological studies will be used to develop testable hypotheses about specific patterns of gene regulation most likely to be causal in drinking behavior

Selected publications:

MILES, M.F., Diaz, J.E. and DeGuzman, V.S. Mechanisms of neuronal adaptation to ethanol: Ethanol induces Hsc70 gene transcription in NG108-15 neuroblastoma x glioma cells. J. Biol. Chem. 266: 2409-2414 (1991).

MILES, M.F., Barhite, S. Sganga, M., and Elliott, M. Phosducin-like protein: An ethanol-responsive potential modulator of guanine nucleotide-binding protein function. Proc. Natl. Acad. Sci. USA 90: 10831-10835 (1993).

Thibault, C., Lai, C., Wilke, N., Duong, B., Olive, M.F., Rahman, S., Dong, H., Lockhart D.F. and MILES, M.F. Expression profiling of neural cells reveals specific patterns of ethanol-responsive gene expression. Mol. Pharm. 52:1593-1600 (2000).

Zhang, L., MILES, M.F., and Adape, K.D. A model of molecular interactions on short oligonucleotide microarrays. Nature Biotech. 21:818-821 (2003).

Elliott, R.C., MILES M.F., and Lowenstein, D.H. Microarray analysis of dentate gyrus gene expression indicates parallel molecular mechanisms contribute to development- and epilepsy-associated neurogenesis and axon outgrowth. J. Neurosci. 23:2218-2227 (2003).

Kerns, R., Ravindranathan, A., Hassan, S., Cage, M.P., Sikela, J.M. and MILES, M.F. Ethanol-responsive brain region expression networks: Implications for behavioral responses to acute ethanol in DBA/2J versus C57BL/6J mice. J. Neurosci., 25:2255-1166 (2005).

Khisti R.T, Wolstenholme J, Shelton K.L., MILES M.F. Characterization of the ethanol deprivation effect in substrains of C57BL/6 Mice. Alcohol 40(2):119-126 (2006).

MILES, M.F. and Williams, R.W. Meta-analysis for microarray studies of the genetics of complex traits. Trends Biotechnol. 25(2):45-47 (2007).
Chen, X., Che, Y., Zhang, L., Putman, A.H., Damaj, I., Martin, B.R., Kendler, K.S., and MILES, M.F. RhoA, encoding a Rho GTPase, is associated with smoking initiation. Genes, Brain and Behavior 6(8):689-697 (2007).

Mulligan, M.K., I. Ponomarev, I., Boehm, II, S.L., Owen, J.A., Levin, P.S., Berman, A.E., Blednov, Y.A. Crabbe, J.C. Williams, R.W., MILES, M.F., and Bergeson, S.E. Alcohol trait and transcriptional genomic analysis of C57BL/6 substrains. Genes, Brain and Behav. 7(6):677-89 (2008).

Guo, A.Y., Webb, B.T., MILES, M.F., Zimmerman, M.P., Kendler, K.S., and Zhao, Z. ERGR: An ethanol-related gene resource. Nucleic Acids Res. 2009 Jan;37(Database issue):D840-5. Epub 2008 Oct 31.
 

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