Neuropathic pain in diabetes or Painful Diabetic Neuropathy (PDN) is a debilitating affliction present in 26% of diabetic patients with substantial impact on their quality of life. Despite this significant prevalence and impact, current therapies for PDN are only partially effective. Moreover, the molecular and electrophysiological mechanisms underlying PDN are not well understood. Neuropathic pain is caused by sustained excitability in sensory neurons which reduces the pain threshold, so that pain is produced in the absence of appropriate stimuli. Sensory neurons display sustained and enhanced excitability in response to different molecules including chemokine's, a large group of proteins with important functions in the nervous system. In particular, research from our laboratory has implicated stromal-derived-factor-1 (SDF-1) and its receptor CXCR4 in the pathogenesis of neuropathic pain in several animal models including focal peripheral nerve axon demyelination and antiviral toxic neuropathy. However, the role of CXCR4/SDF-1 signaling in the pathogenesis of PDN is unknown. My long term goal is to identify the molecular and physiological mechanisms that shape sustained excitability in Dorsal Root Ganglia (DRG) sensory neurons responsible for the transition to PDN. The objective of this application is to investigate molecular and physiological mechanisms of CXCR4/SDF-1 mediated DRG neurons hyper-excitability underlying PDN. The central hypothesis is that CXCR4/SDF-1 signaling mediates enhanced calcium influx and excitability in a subtype of molecularly distinct DRG neurons responsible for PDN. The proposed experiments will achieve the following specific aims.
Aim 1 : To characterize CXCR4 and SDF-1 expressing cells in type II diabetic DRG before and after onset of PDN.
Aim 2 : To ascertain if CXCR4/SDF-1 signaling in DRG sensory neurons is necessary and sufficient for transition to PDN.
Aim 3 : To examine the regulation of sensory neuron excitability by SDF-1 in type II diabetic DRG The proposed research is innovative because chemokine signaling has not been previously implicated in the pathogenesis of neuropathic pain in diabetes. Additionally, the outcomes of these experiments will add to our understanding of how changes in the excitability of sensory neurons contribute to the induction of PDN, which is a critical barrier to progression for effective treatment of this currently intractable and widespread affliction.

Public Health Relevance

Many patients with diabetes also suffer from a chronic pain syndrome called Painful Diabetic Neuropathy (PDN). Current available therapies for PDN are only partially effective and the pathogenesis of the disease is not known. In this proposal, I will study if a group of proteins, called chemokine's, are involved in the pathogenesis of PDN. The results of this investigation will possibly result in new therapies to alleviate the pain of diabetc patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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NST-2 Subcommittee (NST)
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Porter, Linda L
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Northwestern University at Chicago
Schools of Medicine
United States
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Jayaraj, Nirupa D; Bhattacharyya, Bula J; Belmadani, Abdelhak A et al. (2018) Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy. J Clin Invest 128:2205-2225
Menichella, Daniela M; Jayaraj, Nirupa D; Wilson, Heather M et al. (2016) Ganglioside GM3 synthase depletion reverses neuropathic pain and small fiber neuropathy in diet-induced diabetic mice. Mol Pain 12:
Menichella, Daniela Maria; Abdelhak, Belmadani; Ren, Dongjun et al. (2014) CXCR4 chemokine receptor signaling mediates pain in diabetic neuropathy. Mol Pain 10:42