Bimal N. Desai

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Primary Appointment

Associate Professor, Pharmacology

Education

  • PhD, Immunology, Harvard University

Research Disciplines

Biochemistry, Cell and Developmental Biology, Immunology, Microbiology, Molecular Pharmacology

Research Interests

Ion channels and Ca2+-signaling in inflammation, immunity and tissue homeostasis

Research Description

*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 labâs 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 â 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 â 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.

Training

  • Biotechnology Training Grant
  • Interdisciplinary Training Program in Immunology
  • Training in Cell and Molecular Biology
  • Training in the Pharmacological Sciences

Selected Publications

2023

Busey, G. W., Manjegowda, M. C., Huang, T., Iobst, W. H., Naphade, S. S., Kennedy, J. A., . . . Desai, B. N. (2023). Analogs of FTY720 inhibit TRPM7 but not S1PRs and exert multimodal anti-inflammatory effects. JOURNAL OF GENERAL PHYSIOLOGY, 156(1). doi:10.1085/jgp.202313419

Busey, G., Manjegowda, M., Huang, T., Iobst, W., Naphade, S., Kennedy, J., . . . Desai, B. (2023). Novel TRPM7 inhibitors with potent anti-inflammatory effectsin vivo. doi:10.1101/2023.05.22.541802

Seegren, P. V., Harper, L. R., Downs, T. K., Zhao, X. -Y., Viswanathan, S. B., Stremska, M. E., . . . Desai, B. N. (2023). Reduced mitochondrial calcium uptake in macrophages is a major driver of inflammaging. NATURE AGING, 3(7), 796-+. doi:10.1038/s43587-023-00436-8

2022

Yeudall, S., Upchurch, C. M., Seegren, P. V., Pavelec, C. M., Greulich, J., Lemke, M. C., . . . Leitinger, N. (2022). Macrophage acetyl-CoA carboxylase regulates acute inflammation through control of glucose and lipid metabolism. SCIENCE ADVANCES, 8(47). doi:10.1126/sciadv.abq1984

Schappe, M. S., Stremska, M. E., Busey, G. W., Downs, T. K., Seegren, P. V., Mendu, S. K., . . . Desai, B. N. (2022). Efferocytosis requires periphagosomal Ca2+-signaling and TRPM7-mediated electrical activity. NATURE COMMUNICATIONS, 13(1). doi:10.1038/s41467-022-30959-4

2021

Chiu, Y. -H., Medina, C. B., Doyle, C. A., Zhou, M., Narahari, A. K., Sandilos, J. K., . . . Bayliss, D. A. (2021). Deacetylation as a receptor-regulated direct activation switch for pannexin channels. NATURE COMMUNICATIONS, 12(1). doi:10.1038/s41467-021-24825-y

Medina, C. B., Chiu, Y. -H., Stremska, M. E., Lucas, C. D., Poon, I., Tung, K. S., . . . Ravichandran, K. S. (2021). Pannexin 1 channels facilitate communication between T cells to restrict the severity of airway inflammation. IMMUNITY, 54(8), 1715-+. doi:10.1016/j.immuni.2021.06.014

Partida-Sanchez, S., Desai, B. N., Schwab, A., & Zierler, S. (2021). Editorial: TRP Channels in Inflammation and Immunity. FRONTIERS IN IMMUNOLOGY, 12. doi:10.3389/fimmu.2021.684172

2020

Cuddy, S. R., Schinlever, A. R., Dochnal, S., Seegren, P. V., Suzich, J., Kundu, P., . . . Cliffe, A. R. (2020). Neuronal hyperexcitability is a DLK-dependent trigger of herpes simplex virus reactivation that can be induced by IL-1. ELIFE, 9. doi:10.7554/eLife.58037

Mendu, S. K., Stremska, M. E., Schappe, M. S., Moser, E. K., Krupa, J. K., Rogers, J. S., . . . Desai, B. N. (2020). Targeting the ion channel TRPM7 promotes the thymic development of regulatory T cells by promoting IL-2 signaling. SCIENCE SIGNALING, 13(661). doi:10.1126/scisignal.abb0619

Senthivinayagam, S., Serbulea, V., Upchurch, C. M., Polanowska-Grabowska, R., Mendu, S. K., Sahu, S., . . . Leitinger, N. (2021). Adaptive thermogenesis in brown adipose tissue involves activation of pannexin-1 channels. MOLECULAR METABOLISM, 44. doi:10.1016/j.molmet.2020.101130

Seegren, P. V., Downs, T. K., Stremska, M. E., Harper, L. R., Cao, R., Olson, R. J., . . . Desai, B. N. (2020). Mitochondrial Ca2+ Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing. CELL REPORTS, 33(8). doi:10.1016/j.celrep.2020.108411

DeLalio, L. J., Masati, E., Mendu, S., Ruddiman, C. A., Yang, Y., Johnstone, S. R., . . . Isakson, B. E. (2020). Pannexin 1 channels in renin-expressing cells influence renin secretion and blood pressure homeostasis. KIDNEY INTERNATIONAL, 98(3), 630-644. doi:10.1016/j.kint.2020.04.041

Cuddy, S., Schinlever, A., Dochnal, S., Suzich, J., Kundu, P., Downs, T., . . . Cliffe, A. (2020). Neuronal hyperexcitability is a DLK-dependent trigger of HSV-1 reactivation that can be induced by IL-1. doi:10.1101/2020.04.16.044875

Kreutzberger, A. J. B., Kiessling, V., Doyle, C. A., Schenk, N., Upchurch, C. M., Elmer-Dixon, M., . . . Tamm, L. K. (2020). Distinct insulin granule subpopulations implicated in the secretory pathology of diabetes types 1 and 2. ELIFE, 9. doi:10.7554/eLife.62506

2019

Wang, G., Zhang, P., Mendu, S. K., Wang, Y., Zhang, Y., Kang, X., . . . Zhu, J. J. (2020). Revaluation of magnetic properties of Magneto. NATURE NEUROSCIENCE, 23(9), 1047-+. doi:10.1038/s41593-019-0473-5

2018

Serbulea, V., Upchurch, C. M., Schappe, M. S., Voigt, P., DeWeese, D. E., Desai, B. N., . . . Leitinger, N. (2018). Macrophage phenotype and bioenergetics are controlled by oxidized phospholipids identified in lean and obese adipose tissue. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115(27), E6254-E6263. doi:10.1073/pnas.1800544115

Schappe, M. S., Szteyn, K., Stremska, M. E., Mendu, S. K., Downs, T. K., Seegren, P. V., . . . Desai, B. N. (2018). Chanzyme TRPM7 Mediates the Ca2+ Influx Essential for Lipopolysaccharide-Induced Toll-Like Receptor 4 Endocytosis and Macrophage Activation. IMMUNITY, 48(1), 59-+. doi:10.1016/j.immuni.2017.11.026

Schappe, M. S., & Desai, B. N. (2018). Measurement of TLR4 and CD14 Receptor Endocytosis Using Flow Cytometry. BIO-PROTOCOL, 8(14). doi:10.21769/BioProtoc.2926

2017

Good, M. E., Chiu, Y. -H., Poon, I. K. H., Medina, C. B., Butcher, J. T., Mendu, S. K., . . . Ravichandran, K. S. (2018). Pannexin 1 Channels as an Unexpected New Target of the Anti-Hypertensive Drug Spironolactone. CIRCULATION RESEARCH, 122(4), 606-615. doi:10.1161/CIRCRESAHA.117.312380

Chiu, Y. -H., Schappe, M. S., Desai, B. N., & Bayliss, D. A. (2018). Revisiting multimodal activation and channel properties of Pannexin 1. JOURNAL OF GENERAL PHYSIOLOGY, 150(1), 19-39. doi:10.1085/jgp.201711888

Lam, P. -Y., Mendu, S. K., Mills, R. W., Zheng, B., Padilla, H., Milan, D. J., . . . Peterson, R. T. (2017). A high-conductance chemo-optogenetic system based on the vertebrate channel Trpa1b. SCIENTIFIC REPORTS, 7. doi:10.1038/s41598-017-11791-z

Weaver, J. L., Arandjelovic, S., Brown, G., Mendu, S. K., Schappe, M. S., Buckley, M. W., . . . Bayliss, D. A. (2017). Hematopoietic pannexin 1 function is critical for neuropathic pain. SCIENTIFIC REPORTS, 7. doi:10.1038/srep42550

2014

Desai, B. N., & Leitinger, N. (2014). Purinergic and calcium signaling in macrophage function and plasticity. FRONTIERS IN IMMUNOLOGY, 5. doi:10.3389/fimmu.2014.00580

Py, B. F., Jin, M., Desai, B. N., Penumaka, A., Zhu, H., Kober, M., . . . Yuan, J. (2014). Caspase-11 Controls Interleukin-1β Release through Degradation of TRPC1. CELL REPORTS, 6(6), 1122-1128. doi:10.1016/j.celrep.2014.02.015

2012

Desai, B. N., Krapivinsky, G., Navarro, B., Krapivinsky, L., Carter, B. C., Febvay, S., . . . Clapham, D. E. (2012). Cleavage of TRPM7 Releases the Kinase Domain from the Ion Channel and Regulates Its Participation in Fas-Induced Apoptosis. DEVELOPMENTAL CELL, 22(6), 1149-1162. doi:10.1016/j.devcel.2012.04.006