Cellular calcium, ion channels, reactive oxygen species and neurotransmitter receptors are the important signal transduction elements in the cell. These elements may initiate, regulate and maintain a variety of cellular responses such as cell contraction, proliferation, migration, differentiation, gene expression, metabolism and death. Our main research interests are focused on the studies of their molecular geneses, regulatory mechanisms, signaling processes, and physiological roles in vascular, airway, and other muscle cells. We also seek to determine the functional importance of these signal transduction constituents in the development of pulmonary hypertension, asthma, diabetes and hypertension. We pursue these goals using laser scanning confocal microscopic, wide-field calcium imaging, patch clamp, biochemical, molecular biological, pharmacological and genetic (e.g., gene knockdown, knockout and overexpression) approaches at the molecular, cellular, organ and animal levels alongside tissues and cells from patients.
The ongoing research projects in the laboratory include (but not limited):
1) Mechanisms for hypoxic calcium release in pulmonary artery myocytes Intracellular Ca2+ release in smooth muscle cells plays a crucial role in the development of hypoxia-induced pulmonary vasoconstriction and associated pulmonary hypertension, but cellular and molecular processes coupling hypoxia to Ca2+ release are poorly understood. In this research project, we attempt to determine: 1) how hypoxia induces Ca2+ release from intracellular stores; and 2) what the primary oxygen sensors and key signal transducing elements are in hypoxic Ca2+ release. Specifically, we are focused on the roles of ryanodine receptors, inositol triphosphate receptors, FK506 binding protein 12, cyclic ADP-ribose, nicotinic acid adenine dinucleotide phosphate, mitochondria, NADPH oxidase, reactive oxygen species, redox potential and protein kinase C in hypoxic Ca2+ release in pulmonary artery myocytes.
2) Novel signaling for calcium release in airway myocytes Cholinergic nerves provide a predominant neural control of airway smooth muscle cells through muscarinic receptors. Simulation of these receptors activates phospholipase C, and then generates inositol triphosphate, which induces Ca2+ release from the sarcoplasmic reticulum through inositol triphosphate receptors. This research proposal seeks to examine whether: 1) stimulation of muscarinic receptors may result in the activation of ADP-ribosyl cyclase, production of cyclic ADP-ribose, and Ca2+ release through ryanodine receptors, amplifying muscarinic Ca2+ release and associated contraction in airway smooth muscle cells; and 2) the ADP-ribosyl cyclase/cyclic ADP-ribose signaling may contribute to asthmatic airway muscle hyperresponsiveness to muscarinic agonists.
3) Heterogeneity of hypoxic calcium release in pulmonary and systemic artery myocytes Hypoxia induces vasoconstriction in pulmonary arteries, but not systemic arteries. Moreover, hypoxic pulmonary vasoconstriction is much greater in resistance than conduit pulmonary arteries. This research project aims to examine if: 1) subtype ryanodine receptors (RyR1, RyR2 and RyR3) are heterogeneously expressed in resistance and conduit pulmonary as well as systemic artery smooth muscle cells; 2) the heterogeneity in subtype RyR expression underlies functional differences in excitation-contraction coupling and hypoxic Ca2+ release between these cell types; and 3) specific interactions of FK506 binding proteins and cyclic ADP-ribose with different subtype RyRs may play an important role in the functional differences.
4) Expression and roles of FK506 binding protein 12.6 in pulmonary artery myocytes FK506 binding proteins with molecular weights of 12 and 12.6 KDa (FKBP12 and FKBP12.6) are associated with and regulate the skeletal and cardiac ryanodine receptors, respectively. However, little is known about the expression and functions of FKBPs in smooth muscle cells. Our main interests in this proposal are to study: 1) whether FKBP12.6 is expressed and plays a role in hypoxic Ca2+ release in pulmonary artery myocytes; and 2) whether cyclic ADP-ribose mediates the role of FKBP12.6 in hypoxic Ca2+ release in pulmonary artery smooth muscle cells.