Global Assessment of Myeloma Response to Chemotherapy

骨髓瘤化疗反应的整体评估

• 批准号: 8819976
• 负责人: Arun P. Wiita
• 金额: $ 15.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8819976
• 关键词: Address; Advisory Committees; Affect; Aftercare; Apoptosis; Apoptotic; Award; Basic Science; Bioinformatics; Biological; Biological Assay; Biological Markers; Biophysics; Bone Marrow; Bortezomib; California; Cell Death; Cell Line; Cell physiology; Cells; Cellular biology; Chemicals; Clinic; Clinical; Clinical Management; Clinical Research; Coculture Techniques; Collaborations; Combined Modality Therapy; Committee Members; Communities; Complex; Data; Development; Diagnostic Procedure; Disease; Doctor of Philosophy; Evolution; Exposure to; Future; Global Change; Goals; Health; Hematologic Neoplasms; Hematopoietic Neoplasms; Homeostasis; Induction of Apoptosis; Investigation; K-Series Research Career Programs; Knowledge; Laboratories; Laboratory Research; Lead; Maintenance; Malignant Neoplasms; Mass Spectrum Analysis; Medicine; Mentors; Mentorship; Messenger RNA; Methods; Mission; Modeling; Molecular Biology; Molecular Chaperones; Molecular Target; Monitor; Multiple Myeloma; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Physicians; Plasma Cells; Play; Post-Translational Protein Processing; Process; Production; Proteins; Proteomics; Publishing; Records; Regimen; Regulation; Research; Research Personnel; Research Proposals; Residencies; Resistance; Resistance development; Resolution; Resources; Ribosomes; Role; San Francisco; Scientist; Signal Transduction; Stress; Stromal Cells; System; Systems Biology; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Training; Transcript; Translational Regulation; Translations; Ubiquitination; United States National Institutes of Health; Universities; Work; base; cancer cell; cancer proteomics; career; chemotherapy; cost; deep sequencing; drug mechanism; inhibitor/antagonist; insight; killings; novel; novel diagnostics; physical model; response; response marker; single molecule; small hairpin RNA; symposium; therapeutic target; tool; tumor initiation

 DESCRIPTION (provided by applicant): This is a resubmission application for the K08 Mentored Clinical Scientist Research Career Development Award for Dr. Arun Wiita in the Dept. of Laboratory Medicine at the University of California, San Francisco. Dr. Wiita completed his MD/PhD at Columbia University, including highly successful graduate work in single molecule biophysics in the lab of Julio Fernandez, PhD. Since finishing his residency in Laboratory Medicine at UCSF he has been pursuing research in apoptosis in hematologic cancers with Jim Wells, PhD. Despite moving into a very different field, Dr. Wiita has made significant progress on two major projects, one published and the other submitted. His long-term goal is to understand in greater detail how cancer cells evolve and respond to therapies, eventually resulting in new diagnostic tools to assist cancer management. The K08 award will provide Dr. Wiita with the protected time and additional training in bioinformatics, proteomics, and cancer signaling networks critical to his development as a tenure-track physician-scientist primarily devoted to laboratory research. His mentor, Jim Wells, PhD, an expert on therapeutics and cell death, and his co-mentor, Kevin Shannon, MD, an expert on hematologic malignancies, have extremely strong records of mentorship. Additional advisory committee members include Jonathan Weissman, PhD, an expert on systems biology, Al Burlingame, PhD, a pioneer of biological mass spectrometry, and Scott Kogan, MD, a physician-scientist bridging clinical and basic research in Laboratory Medicine. Including coursework and participation in seminars and conferences, Dr. Wiita has drawn on the myriad resources of the UCSF scientific community to promote his career as an independent investigator. The research proposal is centered on using emerging, systems-level technologies to address pressing issues in management of multiple myeloma, an incurable, aggressive hematologic malignancy. In Aim 1 Dr. Wiita has begun to develop a unique pipeline combining mRNA deep sequencing, ribosome profiling, and quantitative proteomics to monitor bortezomib-induced cell death in myeloma cells. These studies have already revealed extensive biological insight into translational dynamics after bortezomib exposure. Here he will expand these studies with new proteomic and analysis methods to monitor the role of post-translational modifications and cellular signaling. In Aim 2 Dr. Wiita will use the first-of-its-kind data obtained in this pipeline to develop a new quantitatie model of protein translation and translational regulation. These processes are key determinants of cellular homeostasis and regulation and also play an important role in myeloma pathogenesis. In Aim 3 Dr. Wiita will use cell and molecular biology approaches to elucidate resistance and response markers as well as combination therapeutic targets in myeloma, driven by hypotheses based on systems-level data. These studies are deeply related to the missions of the NIH and NCI as they will greatly expand our understanding of therapeutic effects in myeloma and, in the future, potentially any malignancy.

 描述（由申请人提供）：这是加州大学旧金山分校检验医学系 Arun Wiita 博士的 K08 指导临床科学家研究职业发展奖重新提交申请。 Wiita 博士在哥伦比亚大学完成了医学博士/博士学位，其中包括在 Julio Fernandez 博士实验室的单分子生物物理学方面取得了非常成功的研究生工作。自从完成加州大学旧金山分校实验医学住院医师实习以来，他一直与 Jim Wells 博士一起从事血液癌症细胞凋亡的研究。尽管进入了一个截然不同的领域，Wiita 博士在两个主要项目上取得了重大进展，一个已发表，另一个已提交。他的长期目标是更详细地了解癌细胞如何进化和对治疗的反应，最终产生新的诊断工具来协助癌症管理。 K08 奖将为 Wiita 博士提供受保护的时间以及生物信息学、蛋白质组学和癌症信号网络方面的额外培训，这对于他作为主要致力于实验室研究的终身教授科学家的发展至关重要。他的导师 Jim Wells 博士（治疗学和细胞死亡方面的专家）和他的共同导师 Kevin Shannon 博士（血液恶性肿瘤方面的专家）拥有极其丰富的指导记录。其他咨询委员会成员包括系统生物学专家 Jonathan Weissman 博士、生物质谱先驱 Al Burlingame 博士以及桥接检验医学临床和基础研究的医师科学家 Scott Kogan 博士。 Wiita 博士利用了 UCSF 科学界的无数资源，包括课程作业和参加研讨会和会议，以促进他作为独立研究者的职业生涯。 该研究提案的重点是使用新兴的系统级技术来解决多发性骨髓瘤（一种无法治愈的侵袭性血液恶性肿瘤）治疗中的紧迫问题。在目标 1 中，Wiita 博士已开始开发一种独特的管道，将 mRNA 深度测序、核糖体分析和定量蛋白质组学相结合，以监测硼替佐米诱导的骨髓瘤细胞细胞死亡。这些研究已经揭示了硼替佐米暴露后转化动力学的广泛生物学见解。在这里，他将利用新的蛋白质组学和分析方法扩展这些研究，以监测翻译后修饰和细胞信号传导的作用。在目标 2 中，Wiita 博士将利用在该管道中获得的首个数据来开发蛋白质翻译和翻译调控的新定量模型。这些过程是细胞稳态和调节的关键决定因素，也在骨髓瘤发病机制中发挥重要作用。在目标 3 中，Wiita 博士将在基于系统级数据的假设的驱动下，利用细胞和分子生物学方法来阐明骨髓瘤的耐药性和反应标记物以及联合治疗靶点。这些研究与 NIH 和 NCI 的使命密切相关，因为它们将极大地扩展我们对骨髓瘤以及未来潜在的任何恶性肿瘤治疗效果的理解。