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Studies of the structural and functional basis of neuroblastoma drug resistance

神经母细胞瘤耐药性的结构和功能基础研究

基本信息

批准号：
10323652
负责人：
Harlan Linver Pietz
金额：
$ 5.18万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323652
关键词：
ABCB1 gene ATP-Binding Cassette Transporters Address American Amino Acids Antineoplastic Agents Antioxidants Binding Binding Sites Biochemical Biological Assay Biophysics Cattle Cell membrane Cells Cellular Assay Characteristics Charge Child Childhood Extracranial Solid Tumor Clinical Clinical Research Communication Complement component C4a Complex Coupled Cryoelectron Microscopy Cyclic Peptides Cytoplasm Development Diagnosis Doctor of Philosophy Doxorubicin Drug resistance Educational Curriculum Environment Equipment Etoposide Event Fellowship Foundations Future Glutathione Glutathione Disulfide Health Promotion Homologous Gene Human Hydrophobicity Institution Laboratories Leukotriene C4 Libraries Ligand Binding Ligands Literature Measures Mediating Medical Medicine Membrane Biology Memorial Sloan-Kettering Cancer Center Mentors Mentorship Methotrexate Molecular Molecular Conformation Molecular Structure Multi-Drug Resistance Mutagenesis Mutation Analysis Natural Products Nature Neuroblastoma New York City Oxides Pathologic Patients Pharmaceutical Preparations Phase Physicians Physiological Plasma Regulation Research Research Training Resources Scientist Site Solid Neoplasm Specificity Structure Supervision Testing Therapeutic Intervention Training Treatment Failure Universities Verapamil Vincristine Work Xenobiotics base career chemotherapeutic agent design disease prognosis disorder risk high risk improved insight multidrug transport novel overexpression particle preservation programs skills structural biology therapeutic development tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Neuroblastoma is the most common extracranial tumor of young children, and the five-year overall survival of children with high-risk disease is less than 50%. Overexpression of multidrug resistance protein 1 (MRP1), a plasma membrane ATP-binding cassette (ABC) transporter, is associated with high-risk neuroblastoma. MRP1 transports multiple neuroblastoma chemotherapeutic agents out of the cell in a glutathione (GSH)-dependent manner. Other MRP1 substrates are transported in a GSH-independent manner, and certain compounds stimulate MRP1-mediated GSH efflux without being transported themselves. The mechanisms of GSH-dependent and GSH-independent MRP1 substrate transport – as well MRP1-mediated GSH efflux – are still not well understood. Specific Aim 1 of this proposal seeks to determine the structural basis of GSH-dependent vs. GSH-independent substrate transport by MRP1 using cryo-electron microscopy coupled with biophysical, biochemical, and cell-based assays for MRP1 function. Specific Aim 2 of this proposal seeks to determine the structural basis of the activation and inhibition of GSH efflux by ligands that regulate MRP1 activity. The successful completion of these aims will fill a gap in the research literature by determining the structural basis for MRP1 substrate poly-specificity, particularly with respect to chemotherapeutic agents used in the treatment of neuroblastoma, and will provide a basis for future therapeutic intervention. The proposed research strategy will be completed under the mentorship of Dr. Jue Chen in the Laboratory of Membrane Biology and Biophysics at The Rockefeller University in New York City. The accompanying fellowship training plan will be completed through the Tri-Institutional MD-PhD Program of Weill Cornell Medicine, The Rockefeller University, and Memorial Sloan Kettering Cancer Center. The exceptional clinical and scientific resources of these environments will facilitate the successful completion of both research and training components. The biochemical, biophysical, and structural biology equipment and expertise available at The Rockefeller University is unparalleled, and trainees are also encouraged to collaborate with other scientists and institutions in New York City’s rich structural biology research network. The Tri-Institutional MD-PhD Program offers a diversity of clinical, research, and extracurricular opportunities for trainees to develop the analytical, technical, communication, and mentoring skills necessary to become an independent physician-scientist. Trainees are encouraged to continuously develop their clinical and scientific skills throughout both medical and graduate phases of the MD-PhD curriculum. This curriculum is supervised by a supportive administration that provides ample guidance for trainees to pursue productive careers promoting the health of the American public.

项目总结/文摘