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Primary Office: St. Louis, MO
BS, Zoology (Honors), Utkal University, Bhubaneswar (India)MSc, Biochemistry, National Diary Research Institute, Karnal (India)PhD, Human Biology (Neuroscience), Faculty of Medicine, University of Erlangen-Nuremberg (Germany)
Fellowship, Postgraduate Institute of Medical Education and Research, ChandigarhFellowship, All India Institute of Medical Sciences, New DelhiFellowship, Department of Pharmacology, School of Medicine, and Department of Neurobiology, Physiology and Behavior, University of California at Davis, CA
Interdisciplinary Graduate Program in NeuroscienceMedical Scientist Training Program
Mechanisms of peripheral pain transduction associated with bone-metastasized prostate/breast cancers, as well as in chronic inflammation
We are investigating distinct modifications in TRP and Nav channels in mammalian sensory neurons by a variety of growth factors, cytokines and peptides released at elevated levels from bone-metastasized prostate/breast cancer cells & the surrounding tumor microenvironment. Sustained modifications in the activity and expression of these channels could lead to constitutive sensitization of neuronal firing in sensory afferents innervating bones, ultimately resulting in chronic pain associated with these metastatic bone cancers. We utilize in vitro mouse sensory neuron cultures, co-cultures of neurons with human cancer cells, immunohistochemistry, biochemistry, cell/molecular biology, Ca2+ imaging, electrophysiology, and in vitro pharmacology to delineate the cellular/molecular mechanistic bases underlying nociceptor sensitization associate with cancer pain. In order to verify these mechanistic bases of chronic pain sensitization in vivo we utilize mouse xenograft models of human prostate/breast cancer bone metastasis for the assessment of a battery of bone-related un-evoked pain behavioral responses. Finally, we employ in vivo pharmacology, as well as use xenografts of human cancer cells in specific gene knockout mice, in order to verify the utility of specific TRP and Nav channels as metastatic bone cancer pain therapeutic targets. Our long-term goal is to target such modifications in TRP and Nav channels for the development of highly specific and efficacious analgesics for the management of cancer pain.
We are also investigating the role of specific inflammatory mediators, such as natriuretic peptides, in the modulation of TRP and Nav channels in mammalian sensory neurons and sensitization of their firing properties, which presumably underlie a peripheral transduction mechanism for inflammatory pain such as arthritis. We utilize similar experimental approach as mentioned above, additionally with the use of mouse models of osteoarthritis to address these questions. Again, our long-term goal is to target specific TRP and Nav channels, and the specific modulations there in for the development of highly specific and efficacious analgesics for inflammatory pain associated with arthritis. For both metastatic bone cancer pain and arthritis pain projects, we envision on developing strategies for specific bone-targeted delivery of combinations of anti-tumor & analgesic, and anti-inflammatory & analgesic drugs for the efficacious management of tumor/bone/joint inflammatory pathologies and the debilitating pain associated with those.
Regulation of neuronal excitability and survival-death dynamics via modulation of Kv channels in mammalian brain neurons during brain tumor induced hyperexcitability, HIV-associated neurodegeneration, and ischemic stroke
We are investigating distinct short- and long-term changes in the expression, localization and functions of Kv channels in mammalian brain neurons by factors/mediators released during ischemic stroke-reperfusion injury, as well as from brain tumor cells, acting through specific GPCRs and growth factor receptors. A number of such modifications in Kv channel localization and function provide cellular plasticity by altering the intrinsic membrane excitability, thereby providing the neurons with a mechanism for neuroprotection. However, distinct long-term modifications in Kv channel expression/ localization/function could also induce neuronal death or neurodegeneration. We are specifically interested in studying the coordinated interplay between distinct Kv channel modulations and membrane excitability in the neuronal soma and dendrites that regulate neuronal survival-death dynamics in response to seizures, ischemic stroke, brain tumor growth, and HIV-associated neurodegeneration & neurocognitive disorders (HAND). We utilize in vitro rodent hippocampal and cortical neuron cultures, co-cultures of neurons with human cancer cells, immunohistochemistry, biochemistry, cell/molecular biology, functional single ion imaging, electrophysiology, and in vitro pharmacology to delineate the cellular/molecular mechanistic bases underlying Kv channel modulations and regulation of membrane excitability upon these neuropathological conditions. In order to verify these mechanistic bases in vivo we plan to utilize mouse middle cerebral artery occlusion model of ischemic stroke-reperfusion injury, rodent xenograft models of human glioma/glioblastoma, as well as the HIV-1 gp120 transgenic mouse model of HAND. Our long-term goal is to target such modifications in specific Kv channels as a convergent point or switch for neuroprotective and neuronal death processes under various hyperexcitable and neurodegenerative pathologies, based on which future pharmacotherapeutic strategies can be developed.
Pain Research Program
Chemokine co-receptor CCR5/CXCR4-dependent modulation of Kv2.1 channel confers acute neuroprotection to HIV-1 glycoprotein gp120 exposure.
2013 August. In Press.
PRICKLE2 defects link the non-canonical Wnt pathway to autism.
2013 May 28. [Epub ahead of print]:doi: 10.1038/mp.2013.71.
Competition between α-actinin and Ca2+-calmodulin controls retention of the L-type Ca2+ channel Cav1.2.
2013 May 8. 78(3):483-497.
Distinct modifications in Kv2.1 channel via chemokine receptor CXCR4 regulate neuronal survival-death dynamics..
The C-type natriuretic peptide induces thermal hyperalgesia through a non-canonical Gβγ-dependent modulation of TRPV1 channel.
The electrically silent Kv6.4 subunit confers hyperpolarized gating charge movement in Kv2.1/Kv6.4 heterotetrameric channels.
SynDIG1: an activity-regulated, AMPA- receptor-interacting transmembrane protein that regulates excitatory synapse development.
2010 January 14. 65(1):80-93.
Interdomain cytoplasmic interactions govern the intracellular trafficking, gating, and modulation of the Kv2.1 channel.
2008 May 7. 28(19):4982-4994.
Graded regulation of the Kv2.1 potassium channel by variable phosphorylation.
2006 August 18. 313(5789):976-979 [KSP & DPM are co-first authors].
Regulation of Ca2+-dependent desensitization in the vanilloid receptor TRPV1 by calcineurin and cAMP-dependent protein kinase.
J Biol Chem.
2005 April 8. 280(14):13424-13432.
Date Last Modified: 04/12/2016 -
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