Comparative Transcriptomics to Identify Key Gene Networks of Diabetic Neuropathy
Diabetes currently affects 29 million Americans, and the incidence is increasing by 5% per year. Diabetic peripheral neuropathy (DPN), the most common complication of diabetes, occurs in approximately 60% of all diabetic subjects. DPN is the leading cause of diabetes-related hospital admissions and non-traumatic amputations in the United States, there is substantial irreparable nerve damage prior to the development of noticeable symptoms. However, there are currently no disease-modifying treatments available for DPN other than glycemic control and symptomatic treatments for pain. Therefore, there is a critical need to identify novel effective therapies for DPN. The overall objectives of this proposal is (1) to identify crucial genes and pathways that underlie the progression of human DPN, and (2) to identify commonly dysregulated critical pathways in both human DPN and animal models of DPN. The rationale for the proposed research is that the identification of shared critical pathways and gene expression signatures between human and mouse DPN will elucidate the core mechanisms of DPN progression and expedite the development of mechanism-based therapeutic agents. We will accomplish the objectives of this proposal by pursuing the following specific aims: Aim 1. Identify dysregulated genes and pathways in human DPN using RNA-Seq. We previously reported that there are distinctive groups of human subjects with regenerative, stable, or degenerative DPN. We will use RNA-Seq to compare the transcriptomic signatures in sural nerves biopsies from subjects with regenerative DPN to subjects with degenerative DPN. Aim 2. Identify commonly dysregulated DPN-associated genes and pathways across species. We will compare the transcriptional regulatory network in human DPN with those identified in various mouse DPN models to provide insight into common pathways underlying DPN across species. We anticipate that the key genes and pathways highly correlated with DPN progression and conserved across species will play crucial roles in the pathogenesis of DPN and serve as primary targets of therapeutic intervention of DPN.

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