Drug Discovery

Laurence Zwiebel, Ph.D.

Professor of Biological Sciences

Cornelius Vanderbilt Chair in Biological Sciences

465 21st Ave. South, Nashville, KY, 37235
(615) 343-1894 (office)

Research Description

The major focus of the laboratory is the characterization of specific genes and their products that control important behavioral processes in the life cycle of eusocial insects and mosquitoes that act as vectors for human disease.

One focus is on host (i.e. blood-meal source) seeking/selection in the mosquito Anopheles gambiae which is the principal vector for malaria in Africa. Malaria is caused by a protozoan parasite of the genus Plasmodium that is transmitted to humans through blood feeding by female Anopheline mosquitoes. In this context, we are examining the molecular events of olfaction as this sense predominates the overall host preference behaviors in mosquitoes and other insects. This aspect of the mosquito's behavior is especially important as it makes a significant contribution to the vectorial capacity of this arthropod vector, as well as playing a similar role in the overall impact of many other insects of economic importance.

The proteins that carry out olfactory signal transduction are present on the inside surface of the olfactory receptor neuron (ORN) dendritic membranes that in insects are located in hair like structures called sensilla. Signal transduction is initiated when odorants (either alone or in complexes with Odorant Binding Proteins) bind to members of seven transmembrane containing odorant receptors (ORs). Originally thought to be G-protein coupled, insect ORs are now almost universally recognized to be novel signaling complexes that combine ligand specificity subunit (conventional ORs) with a widely- expressed, non-conventional OR subunit that most probably acts as a direct ionotropic channel on ORN dendrites- in fruitflies this OR is known as 83b (in light of its position on polytene chromosomes) while in mosquitoes this common component is called OR7. Recent studies in Drosophila (Benton et. al. 2009) have also pointed to the existence of a novel class of chemosensory receptors known as ionotropic receptors (IRs) that have homology to insect glutamate receptors. Current efforts are focused on understanding how ORs, IRs, OBPs and other components of this pathway mediate olfactory signal transduction in anopheline mosquitoes.


We use molecular and informatics based approaches to identify genes that are active in olfactory signal transduction in An. gambiae and other disease vector mosquitoes. The molecular characterization of genes which mediate olfaction in this Anopheline mosquito has started with the generation of cDNA libraries specifically derived from olfactory (i.e. the antennal and maxillary palps) and neural (heads that have been stripped of antennal and maxillary palps) structures of female adult mosquitoes. These hand-dissected structures have been used as substrate for the synthesis of subtracted cDNA libraries using novel PCR based methods that are specifically designed to facilitate the use of picogram amounts of mRNA starting material. More recently we have focused on genomics based approaches that include genome mining and deep sequencing of olfactory transcriptomes that has thus resulted in the isolation of several olfactory genes from An. gambiae that are currently being characterized at the molecular and cellular levels.

Much of the lab's focus is on the molecular, biochemical and functional characterization of ORs An. gambiae (AgORs). Over the years "Team AgOR" has gone from the original characterization of AgORs insofar as their DNA sequence and organization to detailed in vivo expression studies. We have extended this study to include the use of ex vivo expression systems, electrophysiology, cell culture and transgenic insect systems (e.g.Drosophila) in order to study the functional characteristics of AgORs from specific senory appendages to whole genome wide approaches (see publication list).

A long-term objective of our work is the molecular characterization of the olfactory genes in general as well as the mechanisms that which are central in the marked

Selected Publications