Andrew P. Thomas, Ph.D.
Research Interest
Calcium-dependent Signal Transduction and Excitation-Contraction Coupling The laboratory is engaged in research in two distinct areas: 1. Mechanisms of signal transduction in response to hormones and growth factors that act through changes in cytosolic Ca2+, primarily mediated by the inositol 1,4,5-trisphosphate (IP3) receptor and ryanodine receptor intracellular Ca2 channels. 2. Cardiac muscle function and the regulation of excitation-contraction coupling in normal and diseased states. These two research areas are related in terms of many of the techniques used, which include: digital imaging fluorescence microscopy; patch-clamp studies of ion channel function; investigations of second messenger action in permeabilized cells; studies of intracellular organelles using laser scanning confocal microscopy in living cells, and molecular biology approaches to elucidate the function of theses signaling components.
Our work on IP3-dependent signal transduction is directed towards understanding the mechanisms by which [Ca2+]i oscillations and Ca2+ waves are generated in nonexcitable cells, and the consequences of these complex patterns of Ca2+ signaling. Oscillations of [Ca2+]i offer important levels of control over the information conveyed to the cell, including differential activation of Ca2+-dependent processes based on the frequency and shape of the oscillation. The functional importance of Ca2+ waves includes the capability to propagate the [Ca2+]i signal from the site of stimulus detection to intracellular targets, including organelles such as mitochondria and the nucleus, as well as intercellular Ca2+ waves that coordinate multicellular systems. Our studies investigate the subcellular organization of signaling components that give rise to polarized, spatially complex [Ca2+]i signals and the consequences of this spatial and temporal organization for the functional responses of the cell. The laboratory is particularly interested in elemental events that give rise to local Ca2+ signaling, and the transmission of Ca2+ signals to the mitochondria. Calcium signaling to the mitochondria plays an important role in coordinating the activation of oxidative energy metabolism with other calcium-dependent cellular functions. Similar Ca2+ signaling to the mitochondria occurs in cardiac muscle, where it serves to coordinate energy generation with the work of contraction. In addition to our investigations of basic cardiac muscle function and excitation-contraction coupling, we are also interested in the cellular changes following ischemic injury and in response to alcohol, both of which can lead to cardiovascular complications including arrhythmia and impaired contractile function.