Chemotherapy induced peripheral neuropathy (CIPN) poses a major clinical problem due to its oftentimes dose- limiting side effects associated with many commonly employed anti-cancer chemotherapy drugs. The onset of CIPN severely impacts the quality of life of patients, leading to dosages reductions, treatment delay, and even discontinuation of the treatment altogether. Abnormal pain sensations mostly in the feet and hands is one of the main side effects of CIPN. CIPN symptoms can occur prior to reaching the point of causing dose limiting side- effects causing major discomfort and pain. Paclitaxel (PTX) is among the most commonly used cancer drugs that cause peripheral neuropathy which is a debilitating and serious dose-limiting side effect in peripheral neurons. Currently, there are no pharmacological interventions or therapeutic approaches for the treatment of PTX induced peripheral neuropathy (PIPN). To identify therapeutic candidates that prevent PIPN, we carried out a drug screening of FDA approved drugs and identified Fluocinolone acetonide (FA) as a neuroprotective drug capable of mitigating axonal degeneration induced by PTX in vitro and in vivo. Based on our recent publication, the neuroprotection effect of FA may have been attributed to enhanced anterograde mitochondrial trafficking. We demonstrated an innovative imaging method for sub-cellular mitochondria trafficking in neurons that allows for characterization of anterograde and retrograde trafficking. However, the understanding of how other non- mitochondrial organelles and their cargos are trafficked in the context of PIPN is yet to be determined. Likewise, the effect by treatment with FA on non-mitochondria organelle trafficking remains unclear at this time. The identification of specific trafficking of axonal cargos in PIPN, FA co-treatment conditions, and subsequent complement findings with associated signaling mechanisms, are necessary to design effective and safe neuroprotection therapies. In this proposal, we propose 1. To Identify a neuroprotective mechanism of Mitochondria Trafficking, Fusion and Biogenesis enhanced by FA within the Axon in PIPN. 2. To Identify the neuroprotective mechanism of FA in trafficking of non-mitochondrial organelles such as lysosomes, golgi and endoplasmic reticulum in PIPN. The proposed approach will be impactful to identify FA induced directional trafficking of other neuronal organelles to protect axonal degeneration. The research will also propose identification of a possible signaling mechanism associated with FA-enhanced neuroprotection. Collectively, our proposed research will broadly impact the field of characterizing the neuronal subcellular organelle and cargos at play in promoting development of neuroprotection strategies. This R15 project will also expose several undergraduate students to research projects and promote the research development and excellence at UNC Charlotte.