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

• 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
• 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

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/摘要 神经母细胞瘤是幼儿最常见的颅外肿瘤， 患有高危疾病的儿童存活率不到50%。多药耐药蛋白1的过表达 （MRP 1），质膜ATP结合盒（ABC）转运蛋白，与高风险 神经母细胞瘤MRP 1在细胞外转运多种神经母细胞瘤化疗药物， 谷胱甘肽（GSH）依赖的方式。其他MRP 1底物以不依赖GSH的方式运输， 某些化合物刺激MRP 1介导的GSH流出而自身不被转运。的 GSH依赖性和GSH非依赖性MRP 1底物转运机制-以及MRP 1介导的 谷胱甘肽外流-仍然没有很好地理解。本提案的具体目标1旨在确定结构基础 使用冷冻电子显微镜结合的MRP 1的GSH依赖性与GSH非依赖性底物转运 与生物物理，生物化学，和基于细胞的测定MRP 1功能。该提案的具体目标2寻求 确定通过调节MRP 1的配体激活和抑制GSH流出的结构基础 活动这些目标的成功实现将填补研究文献中的空白， MRP 1底物多特异性结构基础，特别是关于所用化疗剂 在神经母细胞瘤的治疗中，并将为未来的治疗干预提供依据。 建议的研究策略将在实验室陈珏博士的指导下完成 他是纽约市洛克菲勒大学的膜生物学和生物物理学教授。所附 奖学金培训计划将通过威尔康奈尔医学的三机构MD-PhD计划完成， 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 这些环境的资源将促进研究和培训的成功完成 件.生物化学，生物物理学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，也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。三机构MD-PhD计划 提供了一个多样化的临床，研究，和课外的机会，为学员发展分析， 技术，沟通和指导技能，成为一个独立的物理学家，科学家。 鼓励受训者在整个医疗和科研过程中不断发展他们的临床和科学技能。 MD-PhD课程的研究生阶段。该课程由支持性管理部门监督， 为学员提供充分的指导，以追求促进美国公众健康的生产性职业。