Graduate School: Harvard University
Primary Appointment: Assistant Professor, Pharmacology
Electrical Signals in Inflamation and Immunity
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? To answer this central question we look to hematopoietic cells for clues. In contrast to most cell types, hematopoietic cells continue to develop and differentiate throughout the mammalian lifespan - providing an ideal model system to study developmental and homeostatic processes. Additionally, this research direction provides a clear path toward tangible biomedical advances. 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 in hematopoietic cells, we hope to gain insights that can be translated into treatment of chronic inflammation and its adverse impact on various diseases.
More specifically, we are identifying ion channels that are tightly regulated during specific cell-fate decisions and characterizing their mechanisms in hematopoietic cells. Of particular interest are the ion channels of the Transient Receptor Potential (TRP) superfamily that are expressed in lymphoid and myeloid lineages. We are interested in questions that probe the specific sub-cellular location, timing and effects of their activity. For some TRP channels, their activity in intracellular membranes (ER, Golgi, lysosomes, specialized vesicles etc.) is of significant interest to us. In the case of T-cells, we are exploring the mechanistic role of TRPM7, a TRP channel with a kinase domain, in regulating T-cell development and homeostasis. In macrophages, we are pinpointing the specific subcellular locations of TRP channels and interrogating their contribution to macrophage activity and maturation. Lastly, we are devising methods to identify novel immunomodulatory ligands that target the ion channels in hematopoietic cells.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 molecular biology, biochemistry, 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.
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