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：
10559501
负责人：
Harlan Linver Pietz
金额：
$ 5.27万
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/10559501
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 Cephalic Characteristics Charge Child Childhood Extracranial Solid Tumor Clinical Collaborations Communication Complement component C4a Complex Coupled Cryoelectron Microscopy Cyclic Peptides Cytoplasm Development Diagnosis Disease Disseminated Malignant Neoplasm Doctor of Philosophy Doxorubicin Drug resistance Educational Curriculum Environment Equipment Etoposide Event Fellowship Foundations Future Glutathione Glutathione Disulfide Health Promotion Homeostasis Homologous Gene Human Hydrophobicity Institution Laboratories Leukotriene C4 Libraries Ligand Binding Ligands Literature Measures Mediating Medical Medicine Membrane 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 Pathologic Patients Peptides Pharmaceutical Preparations Phase Physicians Physiological Productivity Prognosis Regulation Research Resources Scientist Site Solid Neoplasm Structure Testing Therapeutic Intervention Training Treatment Failure Universities Verapamil Vincristine Work Xenobiotics career chemotherapeutic agent design 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.

项目概要/摘要神经母细胞瘤是幼儿最常见的颅外肿瘤，五年来总体发病率多药耐药蛋白1过度表达的高危儿童存活率低于50%。 (MRP1) 是一种质膜 ATP 结合盒 (ABC) 转运蛋白，与高风险相关 MRP1 将多种神经母细胞瘤化疗药物转运出细胞。其他 MRP1 底物以谷胱甘肽 (GSH) 依赖性方式运输。某些化合物可刺激 MRP1 介导的 GSH 外流，但自身不进行转运。 GSH 依赖性和 GSH 独立性 MRP1 底物转运机制以及 MRP1 介导的机制 GSH 外流——目前还没有被很好地理解。该提案的具体目标 1 旨在确定结构基础。使用冷冻电子显微镜耦合 MRP1 的 GSH 依赖性与 GSH 独立性底物转运的比较该提案的具体目标 2 旨在通过生物物理、生物化学和基于细胞的检测来检测 MRP1 功能。确定调节 MRP1 的配体激活和抑制 GSH 外流的结构基础成功完成这些目标将通过确定以下内容来填补研究文献中的空白。 MRP1底物多特异性的结构基础，特别是与所使用的化疗药物有关神经母细胞瘤的治疗，并将为未来的治疗干预提供基础。所提出的研究策略将在实验室陈珏博士的指导下完成纽约洛克菲勒大学膜生物学和生物物理学博士。奖学金培训计划将通过威尔康奈尔医学的三机构MD-PhD项目完成，洛克菲勒大学和纪念斯隆凯特琳癌症中心卓越的临床和科学。这些环境的资源将有助于研究和培训的成功完成 The 提供的生物化学、生物物理和结构生物学设备和专业知识。洛克菲勒大学是无与伦比的，还鼓励学员与其他科学家合作，纽约市丰富的结构生物学研究网络中的机构。为学员提供多种临床、研究和课外机会，培养他们的分析能力、成为一名独立的医师科学家所需的技术、沟通和指导技能。鼓励学员在医学和医学领域不断发展他们的临床和科学技能医学博士-博士课程的研究生阶段该课程由支持性管理部门监督。为学员追求富有成效的职业生涯提供充分的指导，促进美国公众的健康。