Global Assessment of Myeloma Response to Chemotherapy

 描述（由申请人提供）：这是一份重新提交的K 08指导临床科学家研究职业发展奖的申请。加州大学旧金山分校弗朗西斯科的实验医学博士。Wiita博士在哥伦比亚大学完成了他的医学博士/博士学位，包括在Julio费尔南德斯博士实验室的单分子生物物理学研究生工作。自从在加州大学旧金山分校完成了他的实验室医学实习后，他一直在与Jim威尔斯博士一起研究血液系统癌症的细胞凋亡。尽管进入了一个非常不同的领域，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帮助癌症管理。该K 08奖将为Wiita博士提供受保护的时间和生物信息学，蛋白质组学和癌症信号网络方面的额外培训，这对他作为主要致力于实验室研究的终身医学科学家的发展至关重要。他的导师，吉姆威尔斯，博士，治疗和细胞死亡的专家，和他的共同导师，凯文香农，医学博士，血液恶性肿瘤的专家，有非常强的指导记录。其他咨询委员会成员包括系统生物学专家Jonathan Weissman博士，生物质谱学先驱Al Burlingame博士，以及医学博士Scott Kogan，他是连接实验室医学临床和基础研究的医生科学家。包括课程和参加研讨会和会议，Wiita博士利用UCSF科学界的无数资源来促进他作为独立调查员的职业生涯。 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管理中的紧迫问题，多发性骨髓瘤是一种无法治愈的侵袭性血液恶性肿瘤。在Aim 1中，Wiita博士已经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，以监测骨髓瘤细胞中硼替佐米诱导的细胞死亡。这些研究已经揭示了硼替佐米暴露后翻译动力学的广泛生物学见解。在这里，他将扩展这些研究与新的蛋白质组学和分析方法，以监测翻译后修饰和细胞信号的作用。在Aim 2中，Wiita博士将使用该管道中获得的第一批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，并且在骨髓瘤发病机制中也起重要作用。在Aim 3中，Wiita博士将使用细胞和分子生物学方法阐明骨髓瘤中的耐药和反应标志物以及联合治疗靶点，这些靶点由基于系统水平数据的假设驱动。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治疗效果的理解，并且在未来，可能是任何恶性肿瘤。

 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.