Cardiovascular Research Group
Despite many advances in recent years, cardiovascular disease remains the leading cause of death for both men and women. The Cardiovascular Research Group seeks to understand fundamental questions regarding the function and regulation of Ion Channels and the mechanisms controlling the Microcirculation. Multiple molecular, cellular, systems approaches are employed in models ranging from heterologous expression systems, to isolated single cardiac myocytes, to animal models of human disease, to a variety of computational methods.
A common thread linking these diverse approaches and experimental models is the application of biophysical and quantitative methods to understand function at the level of proteins, cells, and tissues. Ultimately, the insights gained will elucidate mechanisms responsible for cardiovascular function in health and disease and may lead to improved therapeutic interventions.
Dr. Clive M. Baumgarten
Dr. Clive M. Baumgarten and his group are focused on understanding the electrical activity of the heart at the cell, membrane, and channel level. Ongoing projects address the regulation of mechanosensitive (stretch-activated) and volume-sensitive (swelling-activated) ion channels in normal cells and cells isolated from hearts in congestive failure. The laboratory has characterized a number of signaling cascades that regulate these channels. For example, we discovered the role of angiotensin II signaling and reactive oxygen species in regulating Cl- channels activated by stretch of integrins and osmotic swelling. In addition, the laboratory developed digital video microscopy methods for identifying the effect of ion transport on cardiac cell volume. This methodology led to the discovery of the role of cGMP and Na/K/2Cl cotransport in cardiac cell volume regulation and characterized the water permeability of cardiac myocytes.
Dr. Diomedes E. Logothetis
Dr. Diomedes E. Logothetis and his group aim to understand ion channel regulation of gating in molecular terms. They are particularly interested in the regulation of ion channel activity by the βγ subunits of GTP-binding (G) proteins and by signaling phosphoinositides in the inner leaflet of the plasma membrane. Studies utilizing electrophysiology and molecular dynamic simulations are probing channel-PIP2 interactions. Post-translational modifications or protein-protein interactions regulate channel activity in a phosphoinositide-dependent manner and do so by targeting sites proximal to the channel-PIP2 amino acid residues. Ongoing studies are aiming to test the hypothesis that modulators of channel activity that depend on phosphoinositides work by adjusting channel-PIP2 interactions. The physiological implications of regulation of channel activity by G proteins and phosphoinositides is studied in model cells and also examined in cardiac and neuronal systems. Disease models of aberrant phoshoinositide regulation in transgenic animals and neuronal cell lines are being explored.
Dr. Roland N. Pittman
Dr. Roland N. Pittman and his group, including Dr. Alexander S. Golub and Dr. Ivo Torres Filho, use state-of-the-art methods to track the movement of oxygen and characterize the hemodynamic and geometric factors that determine oxygen exchange in the microcirculation of striated muscle. Current experimental studies utilize intravital video microscopy and computerized image analysis to obtain the pertinent geometric, hemodynamic and oxygenation data from vascular networks composed of arterioles, capillaries and venules. Phosphorescence quenching and Raman microspectroscopy are used to determine oxygen tension and hemoglobin oxygen saturation in microscopic volumes. The interactions among oxygen, hemoglobin and nitric oxide are investigated in pathophysiological states, such as hypertension, hemorrhage and sickle cell anemia, and with hemoglobin-based and perfluorocarbon oxygen carriers that are used in the treatment of anemia. These experimental approaches are augmented by theoretical modeling studies.
Dr. Gea-Ny Tseng
Dr. Gea-Ny Tseng and her group, including Dr. Min Jiang, are focusing on two interrelated projects. The first addresses structure-function relationships in cardiac voltage-dependent K (Kv) channels and the mechanism of action of pharmacological agents and dietary supplements. Studies of Kv channels seek to build three-dimensional models of delayed rectifier K channels (IKr, hERG; and IKs, KCNQ1/KCNE1) by combining mutagenesis and biophysical/biochemical analyses with computational methods. The second project investigates the mechanisms of 'electrical remodeling' in aging and diseased hearts and how the detrimental effects of electrical remodeling can be ameliorated by pharmacology agents and dietary supplements. Long-chain n-3 polyunsaturated fatty acids (PUFAs, found in fish oils) have been suggested to be protective in patients with heart disease, but there are indications that PUFAs may be detrimental in some cases. Presently the laboratory is characterizing the effects of PUFAs on cardiac electrical activity and remodeling in order to understand whether these agents are pro- or antiarrhythmic.
DR. Lei Zhou
Dr. Lei Zhou and his group focus on the trilogy of structure-dynamics-function for ion channel proteins, specifically, the nature of correlated molecular motions as well as the corresponding changes in response to various external perturbations, such as membrane potential changes and ligand binding. This process begins when an external stimulus triggers changes in the funnel-like protein energy surface, accordingly, the distribution of protein conformation ensemble shifts from the resting state to the activated state. Current research evolves around the protein allostery of ion channels regulated by direct binding of a cyclic-nucleotide (cAMP or cGMP). A multidisciplinary approach including electrophysiology, biochemistry, and computational biology is being applied to test the hypothesis that ion channel’s function closely correlates with not only protein structure but more importantly with protein dynamics. Theoretical approaches being used include normal mode analysis (NMA) and principal component analysis (PCA). Furthermore, coarse-grained computational approaches are being developed to study the effect of surface structural water on protein dynamics. the group studies cyclic-nucleotide activated channels and, in particular, hyperpolarization-activated cyclic nucleotide (HCN) channels found in pacemaker cells in the heart and brain.