Neuroprotection for chemotherapy induced peripheral neuropathy

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.