| Steven J. Sollott, M.D., Senior Investigator Head, Cardioprotection Section Laboratory of Cardiovascular Science E-mail: sollotts@mail.nih.gov |
| Biography: Dr. Sollott received his M.D. from the University of Rochester and completed his residency in internal medicine at a Cornell University program. He subsequently completed his cardiology fellowship at Johns Hopkins University and an NIH medical staff fellowship at NIA's Laboratory of Cardiovascular Science. His research attempts to bridge interests spanning basic and clinical science to therapeutics. |
| Overview: We are studying structure and function of cells from the cardiovascular system along two principal and distinct lines: 1) mechanisms of cardiac contractility, and 2) cellular changes after vascular injury. An underlying theme in both of these areas involves the pursuit and development of single cell biophysical methods to overcome certain limitations and complexities inherent in in vivo and in multicellular in vitro experimental systems, to gain an understanding of basic cell biological processes that may have implications for the pathophysiology and treatment of human disease. |
| Mechanisms of Cardiac Contractility: Principal research efforts, often employing these newly-developed biophysical methods, have focused on the regulation of contractility in intact cardiac myocytes, with particular emphasis on modulation of myofilament contractile activation by novel signaling pathways, for example, via alterations in the balance of specific kinase/phosphatase pathways, via cross-talk between the cGMP- and cAMP-dependent pathways, and via endogenous nitric oxide-dependent mechanisms. Recent work has focused on novel mechanisms of recruitment of contractile activation underlying the Frank-Starling response. |
| Mechanisms of Perturbed Mitochondrial Function in Cardiac Myocytes: Mitochondria play a central role in the regulation of apoptosis, and contribute to the pathogenesis of human degenerative diseases, aging, and cancer. Mitochondrial perturbations can have this result in a number of ways: by disrupting electron transport and energy metabolism, by releasing and/or activating proteins that mediate apoptosis, and by altering cellular redox potential together with the generation of reactive oxygen species (ROS). Recent research is focusing on the relationship between the mitochondrial electrochemical gradient, ROS production, induction of the permeability transition pore, and functional sequella, including ischemia/reperfusion and myocardial preconditioning. |
| Cellular Response to Vascular Injury: The other major research direction involves the investigation of basic cellular responses of vascular smooth muscle cells during gradient-directed chemotaxis, in order to gain insight into fundamental events in the pathogenesis of vascular disease. These experiments with vascular smooth muscle cells have enabled an understanding of how focal receptor-tyrosine-kinase activation coordinates the cascade of signaling traffic and the reorganization of the cytoskeleton, leading to directed migration. Migration of vascular smooth muscle cells from the arterial media to the intima is a key event in the pathogenesis of occlusive vascular disorders, including atherosclerosis and post-angioplasty restenosis. We found that a unique intracellular Ca2+-signaling profile is initiated via extracellular cues provided specifically by gradient exposure to PDGF, achieving an apparent threshold for activation of CaM kinase II (requisite during VSMC chemotaxis), and this phenomenon mediates VSMC chemotaxis. Differences in this specific Ca2+ signaling paradigm among individual cells underlies the asynchronous occurrence rate of chemotaxis seen in VSMC populations. Work is continuing to establish the mechanisms and coordination of subcellular Ca2+-microdomains, compartmentalization of CaM kinase II activation and cytoskeletal rearrangements. |
| These ideas have been applied to the search for strategies to ameliorate the complications of vascular injury. We found that nanomolar levels of paclitaxel (taxol) blocked chemotaxis of VSMC in culture via specific interference with microtubule function, without killing cells. Subsequent in vivo experiments showed that paclitaxel, given systemically to rats at doses achieving blood levels some 2 orders of magnitude below that used in oncologic therapeutics (i.e., averaging well below peak levels of 50 nM), reduces the extent of neointimal proliferation following balloon injury by 70-80% without apparent toxicity. Currently, studies in larger mammals are under way to determine the feasibility of initiating a clinical trial in humans. Also, collaborative efforts are under way pursuing local paclitaxel delivery schemes, such as paclitaxel-coated stents, for this purpose. A microtubule-stabilizing-agent use-patent has been obtained for the applications of paclitaxel (etc.) in treatment of atherosclerosis and restenosis, and a CRADA has been established with private industry partners. |
|
Help Downloading Files on This Page IRP Home What's New Contact Us Accessibility Disclaimer Privacy Site Map NIA Home |
 |
 |
 |