PO Box 800735
Charlottesville, VA 22908
Ion channels and Ca2+-signaling in inflammation, immunity and tissue homeostasis
*Our perspective*: It is generally known that electrical signals lie at the very core of our beating hearts and thinking brains. It may however surprise you to know that the vertebrate embryo itself is forged in a storm of electrical activity, evident from the intensity and periodicity of Ca2+ elevations during early embryogenesis. Nevertheless, the identity and roles of ion channels, the switches that control such electrical signals, during developmental, regenerative and homeostatic processes remain largely unexplored and mysterious. How and to what extent are these electrical switches plugged into cellular physiology and developmental biology of non-excitable cells? *Our goals*: We seek to understand the circuitry of electrical signals at the crossroads of host defense, inflammation and tissue homeostasis. Although the mechanisms used to detect pathogens are well understood, the sensory physiology underlying the rapid functional coordination of immune cells with non-immune cells such as endothelial, epithelial and neuronal cells lacks molecular definition as well as conceptual clarity. A network of ion channels and GPCRs forms the bulwark of sensory physiology across evolutionary scales and systems but their role in guiding inflammatory processes and tissue homeostasis has been understudied because in contrast to neuroscience and physiology, the culture of traditional immunology rarely resonated with that of ion channel biophysics. This historical quirk presents us with a clear gap in knowledge, and an opportunity that suits my lab?s expertise. Moreover, the multifaceted Department of Pharmacology at UVA is an optimal environment to engage these understudied research problems because they require a judicious coalescence of immunology, physiology and neuroscience. Through these endeavors, we aspire to generate the fundamental knowledge necessary to exploit ion channels and transporters in the therapy of autoimmune, inflammatory and neurodegenerative diseases. Because of their easy accessibility on cell membrane and rapid switch-like activity that can be trapped in ON or OFF states, ion channels are the preferred targets of venoms in nature and increasingly, a large number of drugs in the clinic. By identifying, characterizing and manipulating the ion channels involved in inflammation and tissue homeostasis, we hope to gain insights that can be translated into treatment of chronic inflammation and its adverse impact on various diseases. *Current focus*: Myeloid cells are central players in orchestrating host defense and tissue regeneration. We are currently focused on identifying, characterizing and manipulating the key Ca2+-conducting ion channels that play a pivotal role in cell-intrinsic processes of cellular defense upon detection of pathogens or tissue damage. Recently, we identified TRPM7, a Ca2+-conducting ion channel and a serine-threonine kinase, as a key ion channel for macrophage functions during inflammation as well as tissue homeostasis. Since TRPM7 and related TRP channels set an instructional paradigm for how Ca2+ channels regulate macrophage activities, we are studying their regulation and function in considerable molecular detail and in a multiple tissue contexts ? in ex vivo preparations of bone-marrow derived macrophages, in the brain microglia and in the liver-resident Kupffer cells. Concurrently, we are identifying many other Ca2+-channels of salience to myeloid physiology and we are studying how, in conjunction with GPCRs, these Ca2+-conducting channels tailor the cell-intrinsic responses to the ever-changing flux of immunotransmitters in various physiological and pathological microenvironments. In collaboration with multiple groups we are using the specialized toolsets to understand how Pannexin channels mediate the release of immunotransmitter metabolites from dying and inflamed cells. Finally, we are designing or adapting synthetic ion channel actuators to control inflammatory cascades, in the hopes of developing innovative mouse models of inflammation. We are problem-centric in our approach ? learning and utilizing a variety of methods as and when we need them to answer the questions of compelling interest to us. Fast, sensitive and high-resolution live-cell imaging techniques are being combined with conventional cell biology, mouse transgenics, electrophysiology and chemical biology to develop a rich palette of tools and approaches to accelerate our current research and bring into sharper focus, the electrical symphony of life.