MPBC Faculty - Martin Watterson

Our research program is focused on understanding intracellular signal transduction pathways at a molecular level, and the use of this knowledge for the identification of new drug discovery targets. We are primarily focused on calmodulin regulated pathways, the prototype calcium modulated protein for eukaryotic cells, and related members of this protein family. While the biological activity of most of these regulatory proteins is intracellular, some members are released by cells and have intercellular regulatory activity. Relevant to human disease research, certain family members appear to have altered regulation in human pathology. Recently, our efforts have been focused on the calmodulin regulated protein kinases as integrators of eukaryotic cell responses to extracellular stimuli, and as potential drug discovery targets. Along these lines, we have recently developed new algorithms for the mathematical modeling of multiple ligand binding by receptors subject to allosteric regulation, and an approach to the discovery of new classes of enzyme inhibitors by the use of functional genomics linked to recursive combinatorial chemistry. As a next step in the investigation, we interact with a consortium of investigators interested in the development of approaches to peptidomimetic compound development for ligand modulation of biological responses. These approaches are partly motivated by the rapid progress of the various genome projects and their resultant knowledge bases that can be potentially mined for new drug discovery targets. Overall, the approaches to biomedical research questions, the insight into molecular mechanisms, and the reagents produced as a result of these investigations have potential uses in diverse basic biomedical research areas and have relevance to multiple diseases, especially those with complex etiologies or effectors. Our recent discovery of a novel genomic organization paradigm in higher vertebrates has been extended to more detailed mapping of a region of the human genome that has been linked to recombination events. The novel genomic organization paradigm has been extended by us and other investigators to genes that regulate intercellular interactions, cytoskeletal structures, and in vivo integration of signal transduction pathways. Therefore, current investigations include a more extensive characterization of the transcription, translation and subcellular targeting mechanisms critical to vertebrate development and homeostasis. Based on recent progress in linkage of such cellular functions and molecular mechanisms to disease progression and treatment, the more detailed investigation of this new genomic paradigm might provide additional insight into relevant regulatory pathways.

Calmodulin- mediated signal transduction; genetic, cell biology and biophysical approaches Sawkar AR, Lukas TJ, Mirzoeva S, Hibert M, Haiech J, Bourguignon J-J and Watterson, D.M. Development of new classes of low molecular weight and cell permeable inhibitors of serine/threonine protein kinases. FASEB J. 14:A1363 (2000). Van Eldik L.J, Koppal T, Sawkar A.R., Mirzoeva S., Lukas T.J., Hibert M., Haiech, J., Bourguignon, J.J, and Watterson, D.M. Molecular mechanisms and modulation of glial activation: ligand modulation of biological responses mediated by gene-regulating protein kinases. Neurobiology of Aging 21:87 (2000). Kudryashov, Dmistry S., , Chibalina, Margarita V., Konstantin, Birukov G., Lukas, Thomas J., Sellers, James R., Van Eldik, Linda J., Watterson, D.M. Unique sequence of a high molecular weight myosin light chain kinase is involved in interaction with act in cytoskeleton. FEBS Letters 463: 67-71 (1999).	Martin Watterson
	Office Ward 8-196 (312) 503-0656 Lab Ward 8-196 (312) 503-0657 m-watterson@northwestern.edu Our research program is focused on understanding intracellular signal transduction pathways at a molecular level, and the use of this knowledge for the identification of new drug discovery targets. We are primarily focused on calmodulin regulated pathways, the prototype calcium modulated protein for eukaryotic cells, and related members of this protein family. While the biological activity of most of these regulatory proteins is intracellular, some members are released by cells and have intercellular regulatory activity. Relevant to human disease research, certain family members appear to have altered regulation in human pathology. Recently, our efforts have been focused on the calmodulin regulated protein kinases as integrators of eukaryotic cell responses to extracellular stimuli, and as potential drug discovery targets. Along these lines, we have recently developed new algorithms for the mathematical modeling of multiple ligand binding by receptors subject to allosteric regulation, and an approach to the discovery of new classes of enzyme inhibitors by the use of functional genomics linked to recursive combinatorial chemistry. As a next step in the investigation, we interact with a consortium of investigators interested in the development of approaches to peptidomimetic compound development for ligand modulation of biological responses. These approaches are partly motivated by the rapid progress of the various genome projects and their resultant knowledge bases that can be potentially mined for new drug discovery targets. Overall, the approaches to biomedical research questions, the insight into molecular mechanisms, and the reagents produced as a result of these investigations have potential uses in diverse basic biomedical research areas and have relevance to multiple diseases, especially those with complex etiologies or effectors. Our recent discovery of a novel genomic organization paradigm in higher vertebrates has been extended to more detailed mapping of a region of the human genome that has been linked to recombination events. The novel genomic organization paradigm has been extended by us and other investigators to genes that regulate intercellular interactions, cytoskeletal structures, and in vivo integration of signal transduction pathways. Therefore, current investigations include a more extensive characterization of the transcription, translation and subcellular targeting mechanisms critical to vertebrate development and homeostasis. Based on recent progress in linkage of such cellular functions and molecular mechanisms to disease progression and treatment, the more detailed investigation of this new genomic paradigm might provide additional insight into relevant regulatory pathways. Return to Faculty MPBC Home
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