University of California, San Francisco (UCSF)

Molecular Mechanisms of Sensory Neuropathy in Excitotoxicity and Diabetes Models

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Diabetic peripheral neuropathy (DPN) is a common condition that affects half of the diabetic population. As DPN develops, peripheral sensory nerves degenerate progressively from distal nerve endings in the toes and other extremities towards regions closer to the spine. DPN is associated with pain and pain hypersensitivity during early stages, which progresses to loss of sensation and increased risk of injury and amputation. Currently, there is no targeted treatment for the underlying nerve damage, reflecting a lack of mechanistic understanding of these conditions.
Pain-inducing hyperexcitation can cause cellular damage and sensory loss directly, a phenomenon known as excitotoxicity. However, whether it contributes to sensory degeneration elicited by diabetes is not known. Moreover, despite its clinical prevalence and importance, a molecular basis of excitotoxicity in peripheral sensory neurons is lacking. This project aims to systematically dissect the cellular and molecular underpinnings of excitotoxicity to reveal regulatory pathways. These regulators will be further tested for their roles in peripheral neuropathy using pre-clinical DPN models. Results from this study will expand our knowledge of sensory excitotoxicity and its relationship to other excitotoxic conditions, while revealing therapeutic strategies for treating peripheral neuropathies and associated pain syndromes.