Role of PRR14 in Human Sensory Neurons in Oxaliplatin-Induced Peripheral Neuropathy

Project Summary Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and debilitating side effect of cancer treatment, particularly associated with the use of oxaliplatin (OXA), a platinum-based chemotherapeutic agent. Oxaliplatin-induced peripheral neuropathy (OIPN) affects up to 90% of patients undergoing treatment, leading to chronic pain, sensory deficits, and reduced quality of life. Currently, no effective treatments exist to prevent or reverse OIPN, largely due to an incomplete understanding of the underlying molecular mechanisms. Our preliminary RNA sequencing data, has identified Proline-Rich Protein 14 (PRR14) as significantly upregulated in human dorsal root ganglia (DRG) neurons following OXA treatment. PRR14 is implicated in the PI3K-Akt-mTOR signaling pathway, which is crucial for nociceptor plasticity and the pathophysiology of CIPN. These findings suggest that PRR14 may contribute to the electrophysiological changes driving OIPN, representing a novel and unexplored therapeutic target within the druggable proteome. The goal of this study is to investigate the role of PRR14 in OIPN by characterizing its expression, localization, and functional impact in human sensory neurons. We propose two specific aims: 1. Characterize the expression and localization of PRR14 in human DRG neurons: We will perform immunohistochemistry (IHC) on human DRG tissues and immunocytochemistry (ICC) on primary human DRG cultures to map PRR14 protein expression and determine its colocalization with nociceptors following OXA treatment. 2. Determine the effects of PRR14 on the functional response of sensory neurons to OXA: Using RNA interference (siRNA) to knock down PRR14 expression, we will assess neuronal excitability through patch-clamp electrophysiology in cultured human DRG neurons treated with OXA. This research directly aligns with the NIH HEAL Initiative's mission to accelerate the discovery of novel pain targets, specifically within the understudied druggable proteome (PAR-24-197). By validating PRR14 as a key modulator of OIPN, this project aims to pave the way for new therapeutic interventions, improving the quality of life for cancer patients undergoing chemotherapy.