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Mrgprd as a Potential Therapeutic Target for Painful Diabetic Neuropathy

Abdelhak Belmadani, PhD – Research Associate Professor, Northwestern University

Dale S. George, PhD – Postdoctoral Researcher, Northwestern University

Nirupa D Jayaraj, MS – Lab Manager, Northwestern University

Dongjun Ren, MD – Lab Manager, Northwestern University


Background and Aims : Globally, 422 million adults live with diabetes and it is a major global health problem. About 25% of these patients develop painful diabetic neuropathy (PDN), a common debilitating complication of diabetes. Despite the prevalence of the disease, the pathogenesis of the disease is still unclear and the existing therapies are only partly effective. Although it is widely understood that in patients with PDN, nociceptors within the dorsal root ganglion (DRG) become hyperexcitable and eventually degenerate, the molecular mechanism underlying the phenomenon is not known. Our overall aim is to identify changes in the gene expression profile in PDN pathology for the discovery of novel druggable targets.

Methods : In order to understand gene expression changes in PDN, we used a well-established mouse model of type II diabetes. Here, mice were fed with a diet with high content of fat (HFD) for 10 weeks during which these mice become obese, develop glucose intolerance, mechanical allodynia, and small-nerve degeneration. It has been shown that the nociceptive population within the DRG can be molecularly defined by the expression of the sodium channel Nav1.8. Therefore, to specifically study changes to the nociceptive neurons in PDN, we used the Nav1.8::Cre, Ai9 normal and diabetic mice at 10 weeks on diet (Jayaraj et al., 2018). DRGs were harvested and the Nav1.8 positive neurons were then isolated by fluorescence-activated cell sorting. RNA was isolated from this population followed by deep sequencing at a depth of 20-25 million per sample.

Results : We identified 58 overexpressed and 360 underexpressed genes. We observed several GPCRs that were overexpressed including the Mas-related G protein-coupled receptor D (Mrgprd), a gene that has been previously implicated in neuropathic pain. Following this observation, we examined the hairy skin of Mrgprd-EGFP reporter mice and we saw a significant reduction of the intra-epidermal nerve fiber innervation of the Mrgprd neurons in diabetic mice, suggesting an important role of these neurons in PDN. Additionally, Mrgprd positive neurons are a subset of the Nav1.8 population and interestingly, we discovered several of our top candidate genes clustered to the same subpopulation of DRG neurons that are known to express Mrgprd, indicating a functional role of Mrgprd and associated genes in the pathogenesis of nociceptor excitability, neuropathic pain and small fiber degeneration in PDN.

Conclusions : From our analysis, it is evident that RNA sequencing of the Mrgprd subpopulation might offer better resolution of candidate genes. Currently, efforts are directed towards the transcriptomic analysis of Mrgprd neurons, effects of activating inhibitory DREADD receptors targeted to the Mrgprd expressing population of DRG neurons and examining the effects of reducing the expression of Mrgprd receptors using CRISPR based approaches. Overall, we propose Mrgprd as a viable target for the development of new non-opioid, nonaddictive and disease-modifying therapeutics for PDN, a currently intractable and widespread debilitating affliction.

References : N.D. Jayaraj, B.J. Bhattacharyya, A.A. Belmadani, D. Ren, C.A. Rathwell, S. Hackelberg, B.E. Hopkins, H.R. Gupta, R.J. Miller, D.M. Menichella. Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy. J. Clin. Invest., 128 (2018), pp. 2205-2225

Conflicts of Interest : Authors have no conflicts of interest to declare

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