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Investigating the role of MAP2 in chemotherapy-induced peripheral neurotoxicity

Award Number: R01CA275870
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Investigating the role of MAP2 in chemotherapy-induced peripheral neurotoxicity - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $559,858 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	4	12/23/2025	NON-COMPETING CONTINUATION	$559,858
														Subtotal = $559,858

Issue Date FY: 2025 ( Subtotal = $622,064 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	3	1/7/2025	NON-COMPETING CONTINUATION	$559,858
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	3	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	002	3	5/30/2025	NON-COMPETING CONTINUATION	$62,206
														Subtotal = $622,064

Issue Date FY: 2024 ( Subtotal = $550,425 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	2	1/4/2024	NON-COMPETING CONTINUATION	$521,455
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	2	4/16/2024	NON-COMPETING CONTINUATION	$28,970
														Subtotal = $550,425

Issue Date FY: 2023 ( Subtotal = $579,394 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	1	12/27/2022	NEW	$579,394
														Subtotal = $579,394

Grand Total All Awards = $2,311,741

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Investigating the role of MAP2 in chemotherapy-induced peripheral neurotoxicity

Award Number: R01CA275870

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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