Global Assessment of Myeloma Response to Chemotherapy

骨髓瘤化疗反应的整体评估

• 批准号: 8928081
• 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/8928081
• 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; therapy resistant; 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（由应用程序提供）：这是在加利福尼亚大学旧金山分校的实验室医学部Arun Wiita博士的K08指导临床科学家研究职业发展奖的重新提交申请。 Wiita博士在哥伦比亚大学完成了他的医学博士学位/博士学位，其中包括在Julio Fernandez，PhD实验室中在单分子生物物理学领域取得了非常成功的研究生工作。自从在UCSF完成实验室医学的居住下，他一直在吉姆·威尔斯（Jim Wells）博士学位从事血液学癌症的凋亡研究。尽管进入了一个截然不同的领域，但Wiita博士在两个主要项目上取得了重大进展，一个项目已发表，另一个已提交。他的长期目标是更详细地了解癌细胞如何发展和对疗法的反应，最终导致新的诊断工具以帮助癌症管理。 K08奖将为Wiita博士提供受保护的时间和额外的生物信息学，蛋白质组学和癌症信号网络，这对于他作为终身训练的身体科学家至关重要，主要是在实验室研究中。他的心理吉姆·威尔斯（Jim Wells）博士是治疗和细胞死亡的专家，以及他的同事凯文·香农（Kevin Shannon）医学博士，是血液系统恶性肿瘤专家，具有极强的心态记录。其他咨询委员会成员包括乔纳森·韦斯曼（Jonathan Weissman）博士，系统生物学专家，Al Burlingame，博士学位，生物质谱学的先驱，以及医学博士Scott Kogan，医学博士，实验室医学的物理科学桥接临床和基础研究。包括课程工作以及参加半会议和会议，Wiita博士借鉴了UCSF科学界的无数资源，以促进他作为独立调查员的职业。该研究建议集中在使用新兴的系统级技术来解决多发性骨髓瘤的管理问题，这是一种无法治愈的，侵略性的血液系统恶性肿瘤。在AIM 1中，Wiita博士已开始开发独特的管道，结合了mRNA深度测序，核糖体分析和定量蛋白质组学，以监测硼替佐米诱导的骨髓瘤细胞中的细胞死亡。这些研究已经揭示了对硼替佐米暴露后翻译动态的广泛生物学见解。在这里，他将通过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AIM 2中，Wiita博士将使用该管道中获得的首先数据来开发一种新的蛋白质翻译和翻译调节模型。这些过程是细胞稳态和调节的关键决定者，并且在骨髓瘤发病机理中也起着重要作用。在AIM 3中，Wiita博士将使用细胞和分子生物学方法来阐明骨髓瘤的抗药性和反应标记以及组合治疗靶标，这是基于系统级数据的假设驱动的。这些研究与NIH和NCI的任务密切相关，因为它们将极大地扩展我们对骨髓瘤治疗作用的理解，并在将来可能存在任何恶性肿瘤。