Immune cell regulation by swelling-activated ion channels

Project Summary/Abstract Ion channels are proteins that allow the permeation of ions across the plasma membrane. These membrane proteins orchestrate the cellular excitability in neurons and muscle fibers by firing action potentials that are essential for neuronal communication and muscle contraction. In non-excitable cells, such as immune cells, the role of ion channels is much less understood. However, solid evidence demonstrated by null mutations of human or mouse genes have shown that ion channels play critical roles in immune cell function. Here, we aim to study the physiological role of swelling-activated ion channels that are present in T lymphocytes. To achieve this goal, i) we will use a systematic approach to discover the swelling activated Ca2+ (SWAC) channel that is active during the maturation of T lymphocytes and study whether this channel is necessary to provide Ca2+ signals for the positive selection of T cells in the thymus, and ii) study the mechanisms of transport by volume-regulated anion channels (VRACs) for large substrate such as cyclic dinucleotides signaling molecules. We will use cross- disciplinary approaches including functional genomics, systems immunology, electrophysiology, biochemistry and structural biology, and genetic mouse models to understand the complex molecular networks regulated by ion channels in immune cells. The long-term goal of my lab is to identify and characterize novel, specific and functional ion channels in immune cells to gain better understanding of how these proteins regulate the immune response, and make fundamental and translational advances in immunotherapy.