DNA Microarrays in Drug Discovery and Development

Abstract: Messenger RNA (mRNA), a single stranded nucleic acid, serves as the critical intermediary in the transfer of genetic information encoded in the DNA blueprint into a form that can be recognized by the protein synthesis apparatus of the cell. In general, mRNA levels are indicative of the type and amount of proteins made in a cell, and therefore serve as a surrogate indicator of cellular protein levels. Understanding which proteins have altered levels of expression in disease conditions can lead to the identification of novel drug targets.  Current technology prohibits measuring the levels of all the proteins made in a cell; however, a high throughput hybridization methodology using DNA microarrays facilitates the quantification of mRNA levels in an overnight reaction. Microarrays consist of thousands of molecular probes arrayed onto a glass surface or nylon membrane support.  Fluorescently tagged “target” prepared from cellular mRNA is applied to the surface of the array, and each target molecule, representing a unique mRNA in the total population, binds to its cognate DNA probe on the surface of the array. In general the intensity of the fluorescent signal from each probe is indicative of the levels of that specific mRNA in the original sample. Applications for microarrays in the drug discovery process include target identification, compound MOA analysis and toxicity evaluation, identification of genetic polymorphisms, and biomarker identification. 

Dr. Madore was born and raised about 40 miles west of Boston in Auburn, Massachusetts - the site of Dr. Robert Goddard’s famous rocket launch. He received a B.S. in Microbiology from the University of Massachusetts, Amherst in 1984 and a PhD in 1991 in Cellular and Developmental Biology from the State University of New York at Stony Brook. Dr. Madore was a postdoctoral fellow in Dr. Bryan Cullen’s laboratory at the Howard Hughes Medical Institute, Duke University Medical Center from 1991 to 1995 where he worked on the regulation of gene expression in HIV-1. He joined the faculty of the Dermatology Research Unit at the University of Michigan in Ann Arbor in 1995 where he studied the molecular mechanisms of skin photodamage. In 1998 he accepted a position in the Molecular Biology Department at Parke-Davis as leader of the Expression Profiling Group, a position he currently holds in the Pfizer Global Research and Development organization. He is a member of the American Society of Biochemistry and Molecular Biology and on the editorial review board of the Journal of Biological Chemistry. His scientific interests include genomics, eukaryotic transcriptional regulation and RNA processing. Steve is married to Jamie and has 12-year old triplets named Cameron, Mackenzie, and Madison. He enjoys golf, is a youth soccer and hockey coach, and is a USA Hockey registered ice hockey referee.