Current Research Description
A principal goal is to discover novel signaling pathways with relevance to drug addiction and memory functions. We have recently found that calmodulin appears to interact with GPCRs at domains that overlap with G-protein coupling domains fo the receptor. Therefore, calmodulin may represent a previously unrecognized main binding partner for GPCRs, with broad implications for regulation and signaling. This also appears to modulate spontaneous receptor signaling, proposed by us to play a key role in narcotic tolerance and dependence. These studies have led a new approach for the treatment of addiction.
Membrane Transporters, Ion Exchangers, and Ion Channels - These membrane proteins, encoded by multiple diverse gene families containing ~ 1,300 human genes, represent main drug targets, and moreover, determine access of drugs to their target tissues. We plan to establish an integrated map of these membrane proteins as they are epxressed in various tissues and determine electrochemical gradients and transport capacity across lipid membranes. We hypothesize that these functions are critical factors in drug sensitivity and resistance, for example of cancer tissues. As a first step, we are developing a comprehensive custom-design microarray for measuring the expression of essentially all of these genes in cancer cells in vivo and in vitro.
Pharmacogenetics - In another main research direction, we address the question whether genetic factors cause variable drug response between patients, including drug efficacy and toxicity. Our initial focus is on drug transporters, responsible for drug absorption, targeting to diseased tissue, e.g., cancer and penetration of the blood brain-barrier. Ongoing studies also include genetic variants of neurotransmitter receptors. Moreover, we are developing a pharmacogenomics core laboratory to study polymorphisms and gene expression in collaboration with clinical investigators. By applying evolving principles in pharmacogenomics, for example the use of haplotypes and multiple candidate genes, we expect to be able to determine genetic factors in disease progression and therapeutic response.