Our long-term goal is to advance knowledge of the neural mechanisms of chronic pain in SCD and develop an effective pharmacologic treatment. Pain is not only a life-long companion but also a predictor of mortality rate for the 100,000 Americans living with sickle cell disease (SCD), people mainly of African or Latin descent. Though it is now appreciated that SC pain is characterized by chronic pain with episodes of acute pain, the neurobiology of chronic pain is poorly studied, not well characterized, and is refractory to currently available therapies. A potentially fruitful line of investigation to advanc understanding of pain in SCD is the role of cellular signaling mechanisms mediated by serine/threonine protein kinases. Several isoforms of the protein kinase C (PKC) have been implicated in certain chronic pain conditions. We recently reported that PKC? is a critical cellulr regulator sensitizing nociceptors in chemotherapy-induced peripheral neuropathy.12 The latter was inhibited by treatments with PKC? inhibitors or PKC?-siRNA and was absent in PKC?-null mice. In a mouse sickle cell transgenic model (TOW mice), PKC? was found to be significantly activated in the spinal regions relevant for pain and its activity (activation or inhibition) correated with the pain behaviors in TOW mice, thought its exact role remains to be defined. In this proposal, we hypothesize that spinal PKC? is a neuronal mechanism promoting and maintaining the manifestation of chronic pain in SCD. Our strategy is to systematically examine the expression and activity of PKC? in TOW mice using real-time qPCR, cellular trafficking/translocation, immunohistochemistry, immunoblotting and enzymatic kinetics methods, and correlate changes in PKC? expression and activity with the on-set and development of chronic pain (Aim 1). To directly test the hypothesis that spinal PKC? is a molecular mechanism that maintains (Aim 2) and promote (Aim 3) the manifestation of chronic pain in SCD, we will conduct pharmacologic studies by employing complementary approaches to inhibit PKC? (isoform-specific peptide inhibitors, siRNA knockdown, hematopoietic stem cell transplantation, and mouse gene-deletion). Throughout the study, age/sex matched non-sickle wildtype littermate mice will be used as controls. Although the current proposal is mechanistically driven, it may ultimately lead to pharmacological interventions that target the PKC?-pathway for pain in SCD. Having recently moved another kinase inhibitor from bench to a Phase I study in the previous funding cycle, our team is uniquely suited for the (current) mechanistic study and (future) translational work that can ultimately benefit patients with SCD.

Public Health Relevance

Pain and sickle cell disease are so intimately intertwined, that African tribal words for the disease, spoken centuries before Herrick described sickle cell disease (SCD) in the western literature, are onomatopoeic for pain. In spite of it being almost one hundred years since Herrick's paper, the neurobiology of chronic pain in SCD is poorly understood. This study will apply a transgenic SCD mouse model for the study of mechanism and pharmacological treatment based on a protein kinase mechanism. Our long-term goal is to advance knowledge of the neural mechanisms of chronic pain in SCD and develop an effective pharmacologic treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098141-06
Application #
9242067
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Luksenburg, Harvey
Project Start
2009-09-30
Project End
2018-01-15
Budget Start
2017-07-01
Budget End
2018-01-15
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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He, Ying; Wilkie, Diana J; Nazari, Jonathan et al. (2016) PKC?-targeted intervention relieves chronic pain in a murine sickle cell disease model. J Clin Invest 126:3053-7
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Wang, Zaijie Jim; Molokie, Robert E; Wilkie, Diana J (2014) Does cold hypersensitivity increase with age in sickle cell disease? Pain 155:2439-40
Molokie, Robert E; Wilkie, Diana J; Wittert, Harriett et al. (2014) Mechanism-driven phase I translational study of trifluoperazine in adults with sickle cell disease. Eur J Pharmacol 723:419-24

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