Publication Date

2018-07-06

Availability

Open access

Embargo Period

2018-07-06

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Molecular and Cellular Pharmacology (Medicine)

Date of Defense

2018-06-12

First Committee Member

R. Grace Zhai

Second Committee Member

Fulvia Verde

Third Committee Member

Pedro Salas

Fourth Committee Member

Pantelis Tsoulfas

Fifth Committee Member

Yogesh Wairkar

Abstract

The number of individuals living beyond a cancer diagnosis continues to increase due to advances in cancer diagnosis and treatment. Unfortunately, most cancer therapies are associated with a range of complications that can affect the course and completion of treatment as well as patient quality of life. Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of many commonly used chemotherapeutic agents, including the microtubule-targeting agent paclitaxel. Sensory symptoms typically present in the distal extremities and include feelings of numbness, spontaneous pain, and abnormal or exaggerated sensitivity. Currently there are no neuroprotective or effective symptomatic treatments for CIPN. The in vivo mechanisms of CIPN are poorly understood, and the difficulty of identifying cellular drivers of sensory dysfunction in traditional preclinical models remains a challenge to therapeutic translation. In this dissertation, I optimized a model of paclitaxel-induced peripheral neuropathy using Drosophila larvae that recapitulates aspects of chemotherapy-induced sensory dysfunction. I showed that paclitaxel disrupts the organization of microtubule associated MAP1B/Futsch and leads to aberrant stabilization of peripheral sensory dendrites, consistent with its microtubule-stabilizing activity. Importantly, this work supports emerging evidence implicating the terminal sensory endings as a specifically vulnerable site in CIPN. Using this model, I uncovered a critical role for Nmnat in maintaining the integrity and function of peripheral sensory neurons and revealed Nmnat’s therapeutic potential against diverse sensory symptoms of CIPN. These findings establish a simple, yet robust model for studying peripheral mechanisms of CIPN and provide an amenable platform for screening modulators of sensory dysfunction associated with chemotherapy.

Keywords

Nmnat; paclitaxel; chemotherapy; neuropathy; sensory; neuroprotection

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