Dr. Annemieke Kavelaars
The University of Texas MD Anderson Cancer Center
Department of Symptom Research
- Molecular Biology
The overall aim of our studies is to increase our understanding of the pathophysiology of cancer therapy-induced neurobehavioral toxicity, including neuropathic pain, depressed mood, cognitive dysfunction and fatigue, and to apply this newly acquired knowledge to the rational design of novel interventions for alleviating symptom burden in cancer patients. This is important because neurobehavioral deficits as a result of cancer treatment greatly affect patient comfort and functioning, and may lead to lower doses of therapy, treatment holds, and even treatment termination, thus potentially influencing patient survival.
Project 1: A novel neuroimmune mechanism underlying comorbid depression and neuropathic pain
Recent animal studies on development of chronic neuropathic pain and depression in response to nerve injury or chronic inflammation support the hypothesis of common underlying neuroinflammatory mechanisms of these symptoms. Specifically, peripheral immune activation causes sickness behavior (malaise, reduced activity, pain), that can culminate into depressive-like behavior in animals when the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO) is increased.
We discovered that the intracellular kinase G protein coupled receptor kinase 2 (GRK2) possesses anti-inflammatory properties independently of its ability to modulate G protein coupled receptor function. GRK2 acts as a molecular switch that normally prevents the transition from acute to chronic inflammatory pain. At the molecular level, low GRK2 facilitates a pro-inflammatory state, because it enhances the activity of the MAP-kinase P38. This increased p38 activity augments inflammation. p38 activity also regulates IDO expression, which is key to development of inflammation-associated depressive-like and our preliminary data indicate that low GRK2 enhances IDO expression by brain microglia in vitro.
In this project, we use behavioral and immune measures in various KO mouse strains to test the hypothesis that reduced microglial GRK2 caused by the neuroinflammatory response to cancer-therapy increases p38 activity, pro-inflammatory cytokine production and IDO expression, thereby promoting development of neuropathic pain, depressive-like behavior and other neurobehavioral symptoms.
Project 2: A novel molecular switch regulating transition from acute to chronic pain
The second project is based on our recent discovery that GRK2 in sensory neurons is an important regulator of the pain response, in addition to the role of microglial/macrophage GRK2. We showed that cell-specific low nociceptor GRK2 markedly prolongs hyperalgesia induced by prostaglandin E2 (PGE2), without affecting baseline pain sensitivity. Our preliminary evidence indicates that low nociceptor GRK2 causes a switch in cAMP signaling from protein kinase A towards the cAMP target known as “exchange protein directly activated by cAMP” (Epac) and its downstream target PKCe. We now aim at unraveling the molecular pathways by which nociceptor GRK2 contributes to the development of chemotherapy-induced neuropathic pain. Using behavioral, molecular and biochemical approaches we now aim at understanding how GRK2 regulates cAMP to EPAC signalig to promote transition to chronic pain.
Willemen HL, Huo XJ, Mao-Ying QL, Zijlstra J, Heijnen CJ, Kavelaars A. MicroRNA-124 as a novel treatment for persistent hyperalgesia. J Neuroinflammation. 2012 Jun 25;9(1):143
Wang, H., Heijnen, C.J., Eijkelkamp, N., Garza Garbajal, H., Schedlowski, M., Kelley, K.W., Dantzer, R., Kavelaars, A., (2011). GRK2 in sensory neurons regulates epinephrine-induced signalling and duration of mechanical hyperalgesia. Pain, 152:1649-1658
Kavelaars, A., Eijkelkamp, N., Willemen, H.L., Wang, H., Garbajal, A.G. & Heijnen, C.J., (2011). Microglial GRK2: A novel regulator of transition from acute to chronic pain, Brain Behavior and Immunity, 25:1055-1060
Willemen, H.L.M., Eijkelkamp, N., Wang, H., Dantzer, R., Dorn, G.W., Kelley, K.W., Heijnen, C.J., Kavelaars, A., (2010). Microglial/macrophage GRK2 determines duration of peripheral IL-1 beta-induced hyperalgesia: Contribution of spinal cord CX3CR1, p38 and IL-1 signaling. Pain 150:550-560
Eijkelkamp, N., Wang, H., Garza Garbajal, A., Willemen, H.L.M., Zwartkruis, F.J., Wood, J.N., Dantzer, R., Kelley, K.W., Heijnen, C.J., Kavelaars, A. (2010). Low nociceptor GRK2 prolongs PGE2 hyperalgesia via biased cAMP signalling to Epac/Rap1, PKCε and MEK/ERK. Journal of Neuroscience 30:12806-12815
Eijkelkamp, N, Heijnen, C.J., Willemen, H.L., Deumens, R., Joosten, E.A., Kleibeuker, W., Hartog, I.J. den, Velthoven, C.T. van, Nijboer, C., Nassar, M.A., Dorn, G.W. 2nd, Wood, J.N., Kavelaars, A., (2010). GRK2: a novel cell specific regulator of inflammatory pain. Journal of Neuroscience, 30:2138-2149.