Peripheral neuropathies are major neurological complications of multiple chemotherapy drugs causing significant morbidity affecting quality of life and potentially altering life-saving chemotherapy regimens. Many chemotherapy drugs with diverse mechanisms of actions cause axonal degeneration and the underlying mechanisms that lead to distal axonal degeneration, a common feature of most peripheral neuropathies are poorly understood. Furthermore, currently there are no therapies aimed at preventing, reversing or slowing the progression of peripheral neuropathies that cause chronic neuropathic pain, sensory loss and weakness. In this grant we will approach this problem in two ways.
In aim 1, we will examine the molecular mechanisms of distal axonal degeneration induced by paclitaxel as it relates to various pathways that have been linked to Wallerian degeneration.
In aim 2, we will examine the molecular mechanisms of a novel neuroprotective compound, ethoxyquin. Recently, we have identified ethoxyquin as a novel neuroprotective compound that interferes with chaperone activity of heat shock protein 90 (hsp90) and prevents distal axonal degeneration induced by a variety of molecular insults, including paclitaxel. Completion of these studies will give us a better understanding of mechanisms of distal axonal degeneration in chemotherapy-induced peripheral neuropathy and help further explore a novel therapeutic target that can be taken to clinical studies in a timely manner.

Public Health Relevance

Nervous system involvement has remained as one of the most important complications of chemotherapy despite development of novel and more effective anti-cancer therapies. Furthermore, there are no effective therapies that prevent or reverse axonal degeneration seen in chemotherapy- induced peripheral neuropathies. This study is aimed at understanding how peripheral nerves degenerate with paclitaxel, a widely used chemotherapy drug and develop new therapies to prevent it.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS091260-05
Application #
9765421
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Nuckolls, Glen H
Project Start
2015-09-01
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Turkiew, Elliot; Falconer, Debbie; Reed, Nicole et al. (2017) Deletion of Sarm1 gene is neuroprotective in two models of peripheral neuropathy. J Peripher Nerv Syst 22:162-171
Zhu, Jing; Carozzi, Valentina Alda; Reed, Nicole et al. (2016) Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity. Sci Rep 6:28861