Investigating the role of MAP2 in chemotherapy-induced peripheral neurotoxicity

研究 MAP2 在化疗引起的周围神经毒性中的作用

• 批准号: 10559108
• 负责人: Nathan P Staff
• 金额: $ 57.94万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559108
• 关键词: Afferent Neurons; Applications Grants; Area; Axon; Axonal Transport; Bioinformatics; Bortezomib; Cell Line; Chemotherapy-induced peripheral neuropathy; Clustered Regularly Interspaced Short Palindromic Repeats; Complication; Development; Dissection; Dose; Dose Limiting; Drops; Exposure to; Genetic Engineering; Glutamate-ammonia-ligase adenylyltransferase; Grant; Human; Human Biology; Investigation; Link; Malignant Neoplasms; Mediating; Microtubule-Associated Protein 2; Microtubule-Associated Proteins; Microtubules; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Neurons; Nicotinamide Mononucleotide; Numbness; Paclitaxel; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nervous System; Peripheral Nervous System Diseases; Play; Process; Proteasome Inhibitor; Proteins; Proteomics; Role; Series; Signal Pathway; Spinal Ganglia; Sterility; System; Technology; Testing; Therapeutic; Time; Vincristine; axonal degeneration; chemotherapy; clinically relevant; disease-in-a-dish; effective therapy; experimental study; human adult stem cell; induced pluripotent stem cell; innovation; knock-down; neuroprotection; neurotoxic; neurotoxicity; novel; overexpression; phosphoproteomics; prevent; side effect; therapeutic development

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.

项目总结/文摘