Project Details
Description
PROJECT SUMMARY/ABSTRACT
Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect that causes morbidity
and limits the dose of chemotherapy allowed to treat cancers. In most classes of neurotoxic
chemotherapeutics, CIPN manifests as damage to dorsal root ganglia sensory neurons. The
neuronal damage is thought to be due to an unelucidated combination of dysfunctional microtubules,
axonal transport and mitochondria that ultimately leads to programmed axonal degeneration via a
nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) and Sterile Alpha and TIR Motif
Containing 1 (SARM1) pathway. The link between these processes, however, remains entirely
unknown.
Using a human induced pluripotent stem cell (iPSC)-derived dorsal root ganglia sensory neuronal
culture system (iSN), we have identified microtubule-associated protein 2 (MAP2) as a key
determinant of CIPN. When exposed to clinically-relevant doses of bortezomib, paclitaxel or
vincristine, MAP2 levels drop and there is subcellular MAP2 mislocalization in iSN that occurs prior to
axonal degeneration. Critically, overexpression of MAP2 is protective for bortezomib-induced
neurotoxicity in iSN.
In this grant application, we propose to further dissect the role of MAP2 in CIPN by utilizing an
innovative CRISPR-ErCas12a system to develop genetically-engineered iPSC lines that
fluorescently-tag either MAP2 or NMNAT2. These novel iPSC lines will allow for detailed analyses of
the time course of altered subcellular localization and axonal transport, and how these processes link
to SARM1 activation and axonal degeneration. Furthermore, we will investigate the overlapping
mechanisms in CIPN due to bortezomib, paclitaxel, and vincristine using our previously successful
proteomics analysis approach, which now will employ a state-of-the-art quantitative proteomic and
phosphoproteomic technology. The proposed Specific Aims build on existing understanding of the
pathomechanisms of CIPN while innovating into unexplored novel areas that are potential targets for
preventative therapeutic development.
Status | Active |
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Effective start/end date | 1/1/23 → 12/31/24 |
Funding
- National Cancer Institute: $521,455.00
- National Cancer Institute: $579,394.00
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