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Understanding EPHA5 signaling in the effects of paclitaxel-induced peripheral neuropathy on human-induced pluripotent stem cell derived sensory neurons

Grant number: 18/00070-2
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): June 25, 2018
Effective date (End): June 24, 2019
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Priscila Gava Mazzola
Grantee:Amanda Canato Ferracini
Supervisor abroad: Deanna L. Kroetz
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Local de pesquisa : University of California, San Francisco (UCSF), United States  
Associated to the scholarship:16/22335-2 - Evaluation of genetic markers and quality of life in women with ovarian carcinoma, BP.DR

Abstract

Paclitaxel is an antineoplastic drug frequently effective in first line treatment for ovarian, breast, lung and prostate cancer. However, cumulative dose of this agent is a significant predictor of sensory peripheral neuropathy. The first genome wide association studies on paclitaxel induced peripheral neuropathy (PIPN) identified a genetic variant in the ephrin receptor gene EPHA5 associated with increased risk of developing this toxicity. Furthermore, the application of human-induced pluripotent stem cell (iPSC) technology holds the potential for rapid advances in understanding PIPN on molecular level. The propose of this study is to assess the relevance of EPHA5 in the molecular mechanisms underlying PIPN, using a novel human-induced pluripotent stem cell derived sensory neuron model. Human isogenic induced pluripotent stem cell lines will be differentiated into nociceptor sensory neurons (iPSC-SNs) to study paclitaxel effects in the cellular target of toxicity. CRISPRi technology and pharmacological agents will be used to inhibit EPHA5 and the Rho GTPases and measure effects on neurite morphology. All experiments will be repeated a minimum of three times with at least three technical replicates per experiment. Dose-dependent effects of paclitaxel on quantitative measures of neurite morphology will be tested for significance (P < 0.05) using ANOVA followed by a Dunnett's post hoc multiple comparison test; the dependence of these measures on EPHA5 and Ephexin-1 will be similarly tested.