Bacteriophages provide classical models of gene regulation and are of renewed interest in relation to antibiotic therapy and prophage-associated toxogenic infections. Our studies focus on RNA-mediated transcriptional control in lambdoid phages. The transition between immediate-early and delayed-early gene expression is regulated by antitermination protein N. Regulation is mediated by an RNA enhancer in the nascent mRNA. Such studies reveal general principles of adaptive RNA-peptide recognition and RNA-mediated signaling.

Sexual dimorphism -- the difference in body plan between males and females -- provides a model of a genetic switch in metazoan development. Genetic determinants have been defined in diverse organisms by analysis of intersex phenotypes, including human sex reversal. Our studies focus on conserved DNA-binding motifs that regulate male-specific gene expression. Mutations associated with sex reversal are utilized as probes of structure and function.

Diabetes mellitus represents a heterogeneos group of diseases characterized by impaired insulin secretion by the pancreatic b-cell relative to the demands of metabolic homeostasis. Our studies focus on two aspects of diabetes research. The first investigates the role of b-cell transcription factors in glucose-stimulated insulin secretion. Mutations in such factors are a monogenic cause of diabetes mellitus in humans. The second set of studies investigates the folding and dynamics of insulin; applications include design of novel analogs to improve insulin replacement therapy in clinical medicine.

NMR and optical spectroscopies enable the biophysical characterization of protein folding, dynamics and stability. Our studies employ the total synthesis of proteins or nucleic acids to introduce novel probes or unnatural amino acids to decipher the relation of dynamics to structure and function. Of particular interest is the combined application of time-resolved flourescence resonance energy transfer (FRET) and heteronuclear NMR to characterize long-range and local motions in protein-nucleic acid complexes. Comparative studies of native and mutant complexes seek to assess the importance of motions in transcriptional regulation.