A major dose-limiting factor for many chemotherapeutic drugs is the induction of peripheral neuropathy which can cause significant axon damage and neurological deficits in cancer patients. As chemotherapeutic drugs are designed to primarily affect pathways that are active in mitotic cells, such as mitosis and DNA replication, the fact that many of these drugs induce axon degeneration in postmitotic neurons is unexpected and its mechanisms remain largely unknown. In this proposal, my goals are to focus on the frontline drug cisplatin (a DNA damaging agent which has been clinically been shown to induce peripheral neuropathy) and to investigate the mechanisms by which this genotoxic chemotherapeutic drug specifically induces axon degeneration. Studying axon degeneration independently of neuronal death is important because often chemotherapy-induced peripheral neuropathy results from axonal degeneration without any significant loss of the cell bodies. My innovative approach is to use microfluidic technology which allows me to expose only the axons (and not the cell body) to this DNA damaging drug. Indeed, I have established that exposure of cisplatin to exclusively the axons in microfluidic chambers induces widespread axonal degeneration without affecting the cell bodies in peripheral neurons. In this proposal, I will investigate the mechanism by which cisplatin trigger axon degeneration in the absence of nuclear DNA damage. Specifically, in Aim 1, I will determine whether cisplatin acts on axonal mitochondria to induce mitochondrial DNA damage and dysfunction, leading to axon degeneration.
In Aim 2, I will determine the mechanism by which cisplatin induces axon degeneration by focusing on three specific degenerative pathways: the apoptotic, necroptotic, and Wallerian degeneration pathways. My innovative approach of isolating neuronal axons using microfluidic chambers allows me the unique ability to test nuclear damage-independent mechanisms of peripheral neuropathy and provides me an opportunity to uncover unanticipated mechanisms by which chemotherapeutic drugs induce axon degeneration.
The primary goal of this study is to determine the mechanism by which chemotherapeutic drugs used in cancer treatment cause nerve (axon) damage. The damage caused by these drugs to the (peripheral) nervous system can result in significant axon damage resulting in severe pain, loss of sensation, loss of motor control, and other serious neurological deficits in cancer patients which can considerably reduce quality of life during treatment. Thus, understanding the mechanism by which these drugs induce axon damage and degeneration in peripheral neurons is critical for the development of effective cancer therapy that does not result in neurotoxicity.
|Geden, Matthew J; Deshmukh, Mohanish (2016) Axon degeneration: context defines distinct pathways. Curr Opin Neurobiol 39:108-15|
|Cliffe, Anna R; Arbuckle, Jesse H; Vogel, Jodi L et al. (2015) Neuronal Stress Pathway Mediating a Histone Methyl/Phospho Switch Is Required for Herpes Simplex Virus Reactivation. Cell Host Microbe 18:649-58|