The foundation of my research program has been based primarily on the gram-positive, sporeforming bacterium Bacillus thuringiensis. This bacterium produces a parasporal glycoprotein crystal during sporulation that is toxic to a variety of insect pests. The glycoprotein is a protoxin that is activated after ingestion by an insect susceptible to the toxic product. The protoxin (~130 kDa) is processed proteolytically to yield a smaller toxic component (~65 kDa) in the alkaline midgut of the insect. There is a variety of subspecies of B. thuringiensis that exhibit highly specific toxic activity against lepidopteran (moth), dipteran (mosquito), and coleopteran (beetle) larave as well as to some root-knot nematodes. Insecticidal activity is mediated through binding of toxin to a cadherin-like receptor located on the apical membrane of midgut columnar epithelial cells. The interaction of toxin with receptor causes disorder in the normal physiological function(s) of the epithelial cells, leading to colloid osmotic lysis of the cells.

A toxin receptor, BT-R1, has been cloned from the tobacco hornworm Manduca sexta (the model system employed in my laboratory), and, the specific site to which the toxin binds has been defined. The receptor is a 210-kDa protein with striking resemblance to E-cadherin, a protein required to maintain normal cell structure, polarization and function. E-cadherin is a cell-cell adhesion protein located in tight junctions between epithelial cells and is a member of a complex set of proteins that regulate structure, polarity and function of the apical membrane. Perturbation of this set of proteins is lethal to the cell. Research in my laboratory has provided important insights into the molecular biology of the digestive system of insects. The most useful outcome of the research, to date, is an understanding of the delicate intra- and extracellular physiological balance that must be maintained by epithelial cells in the midgut of insects, and, how disruption of this balance can be used advantageously to produce environmentally friendly biopesticides.

The overall objective of my research is to add important and significant information to the knowledge base of invertebrate molecular biology with the goal in mind of designing new and novel products, methods and technologies that will be effective and useful in controlling agriculturally and biomedically important insects. The research expands the spectrum of biopesticides beyond B. thuringiensis to include pesticidal materials that will control a variety of pests. Heterologous invertebrate systems are being used to identify and validate potential gene targets such as receptors, hormones, and regulators of biological functions, and, whose impairment adversely affects normal development, differentiation and morphogenesis of vital organs and tissues associated with food digestion, reproduction, respiration and central nervous system activities, among others. The scientific approach takes advantage of the warehouse of knowledge for Drosophila and Caenorhabditis elegans. Several developmental marker proteins and their mutants from these organisms are well characterized. Homologues of some of these markers have been discovered and characterized in mice, rats and humans, suggesting that they are common in the animal kingdom. However, few of these markers have been studied in insects other than Drosophila. The molecular techniques for identifying these homologues are readily available. A viable option is to utilize functional genomics technology to discover and characterize these homologues in agriculturally and biomedically important insects.