Chronic pain is a prevalent neurological disorder without a safe and efficacious treatment. In particular, painful peripheral neuropathies afflict 6 million Americans annually and pose a daunting, growing healthcare problem. Due to increased survival of chemotherapy patients and a rise in the prevalence of diabetes, the prevalence of painful peripheral neuropathy will likely drastically increase. Therefore, basic research is necessary to identify and validate molecular targets that can be modulated pharmacologically to restore normal sensation by attenuating pain and promoting nerve regeneration. ERK1/2 signaling is a promising target based on recent studies using in vivo pain models and both in vitro and in vivo regeneration models that suggest its inhibition may be able to both attenuate pain and promote nerve regeneration. Therefore, I propose to directly test whether pharmacological inhibition of ERK1/2 signaling can simultaneously accomplish both using a well- characterized in vivo model of chemotherapy-induced neuropathy that is directly relevant to the clinical condition. However, knockout studies provide conflicting results on the role of ERK1/2 signaling throughout life in maintaining neuron number and epidermal innervation. Since pharmacological inhibition of ERK1/2 signaling is already in clinical trials for other disorders and could also be an efficacious treatment for chronic pain particularly painful neuropathy, I propose to investigate whether pharmacological inhibition of ERK1/2 signaling adversely affects neuronal survival and epidermal innervation. Together, these studies will determine whether inhibition of ERK1/2 signaling is potentially an efficacious and safe treatment particularly for painful neuropathy.

Public Health Relevance

Without a safe and effective treatment, chronic pain afflicts millions of Americans annually adversely affecting patient's quality of life and costing our economy billons in treatment and lost productivity. Painful peripheral neuropathy, a type of chronic pain, currently afflicts 6 million Americans annually and will likely become more prevalent in the coming years due to increased prevalence of chemotherapy- and diabetic-induced neuropathy. To address this growing problem, studies are needed to gain insight into the molecular mechanisms of neuropathy and to test potential drug targets for their efficacy and safety in restoration of normal sensation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F02B-D (20))
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Porter, Linda L
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Washington University
Schools of Medicine
Saint Louis
United States
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O'Brien, Daniel E; Alter, Benedict J; Satomoto, Maiko et al. (2015) ERK2 Alone Drives Inflammatory Pain But Cooperates with ERK1 in Sensory Neuron Survival. J Neurosci 35:9491-507