| Laboratory of Clinical Investigation | |
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Josephine M. Egan, M.D., Acting Chief
Senior Investigator |
| Overview: The Laboratory of Clinical Investigation (LCI) is comprised of 4 Sections with 5 principal investigators. These are as follows: Bioanalytical Chemistry and Drug Discovery Section; Diabetes Section; Molecular and Clinical Pharmacology Section; and Magnetic Resonance Imaging and Spectroscopy Section. The common theme and thread among these research groups is that of the identification and development of new therapeutic targets for the treatment of age-related disease. The Laboratory serves as an infrastructure to facilitate the creation and development of therapeutic targets within the Laboratory and across the Intramural Research Program. Activities relating to this theme within each Section are as follows: |
| Bioanalytical Chemistry and Drug Discovery Section (BCDDS): (PI Dr. Irving Wainer) In addition to the original science using receptor-immobilized columns and receptor structural modeling, this Section serves as a resource for determination of drug and metabolite structure and quantitation and for assignment of structure to larger proteins. It therefore conducts receptor/target conformational studies that provide the basis for understanding drug and receptor interactions. A goal is the creation and/or modification of drug structure that optimizes ligand (drug) receptor interactions. Use of receptor-immobilized columns for the nicotinic receptor, for example, is leading to better understanding of the on-off kinetics for various ligands that, coupled with animal or clinical pharmacodynamic data, suggest structural modification of known ligands or prediction of structure for ligands to be synthesized to achieve improvement in ligand-receptor binding characteristics. Similar studies are underway with the drug transporter, P-glycoprotein, and are beginning, in collaboration with Dr. Rui-Ping Xiao in the Laboratory of Cardiovascular Science, on the b2-adrenergic receptor. |
| Diabetes Section (DS): (PIs Drs. Josephine Egan and Michel Bernier) Type 2 diabetes mellitus and the identification of new targets for its treatment are the focus of this Section as it relates to drug discovery and development. Dr. Egan has identified the GLP-1 receptor as a promising target as an insulinotropic agent. In the past Dr. Egan has shown in preclinical and clinical study that the GLP-1 receptor ligand exendin-4 may provide a new approach for the treatment of Type II diabetes mellitus. This work has provided the scientific basis, both preclinical and clinical, that has made this therapeutic target and drug attractive to the private sector, where it is now in later stages of clinical development. The present focus is the study of the mechanisms of the release of enteric peptides that modulate insulin release, and an in-depth study of one of the peptides, GIP, and its receptor, to further understand the role of insulinotropic treatments for type 2 diabetes mellitus. |
| Dr. Bernier focuses on the insulin receptor. He works to elucidate the protein-protein interactions that make up the signaling unit of the insulin receptor, any part of which may be disrupted in type 2 diabetes mellitus. |
| Molecular and Clinical Pharmacology Section (MCPS): (PI Dr. Nikolai Soldatov) In the process of understanding gating mechanisms of the L-type calcium channel and the role of the intracellular domains of the channel in signal transduction, splice variations that change channel function in age and atherosclerosis were noted. Understanding the functional consequence of such splice variation and the changes in local cellular milieu associated with this splice variation has become a new focus of investigation. How these splice variant calcium channels change the pharmacodynamics of calcium channel antagonist drugs may provide understanding of intertissue and interindividual variation in response to these drugs. This is now a translational research effort as well to explore the clinical consequences of such splice variation. A component of identification of a therapeutic target in addition to selection of optimal ligand(s) to move forward as drug candidates is understanding pharmacokinetic/pharmacodynamic properties of these compounds in animal models and man. Present efforts are to develop systems to characterize and predict dose/effect relationships that have utility when neither drug concentration nor drug effect will be available at the time drug dose must be selected for an individual patient. The approach showing promise is with use of trained neural networks. A related area is that of understanding drug dose and concentration/effect relationships when the effect baseline is nonstationary (e.g. blood pressure, heart rate, mental status, WBC or platelet count). Beat-to-beat heart rate variability, and analysis of such data simultaneously in the time and frequency domains using wavelet analysis is the approach being developed. |
| Magnetic Resonance Imaging and Spectroscopy Section (NMR): (PI Dr. Richard Spencer) This Section has and continues to make important contributions in the study of chrondrocyte biology using tissue bioreactors in cellular models of arthritis. With respect to identification of new therapeutic targets and drug development, the major effort is in characterization (phenotyping) of transgenic mice, studies of tissue bioenergetics in various animal disease models, study of body composition and organ function, and evaluating the effects of treatments in the disease models. Collaborations with Dr. Egan, evaluating diabetes animal models, and with Dr. Lakatta in the Laboratory of Cardiovascular Science, studying heart failure models, have been quite informative and productive. Planned studies with Dr. Francomano in the Laboratory of Genetics to characterize the phenotype of transgenic animals that model human skeletal dysplasias, and with Dr. Soldatov in the Molecular and Clinical Pharmacology Section to study the consequences of variant L-type calcium channels on cardiac and vascular function are expected to produce animal models in which therapeutic interventions can be implemented and pharmacodynamics sensitively measured using in vivo NMR. |
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