Global Assessment of Myeloma Response to Chemotherapy

 描述(由申请者提供)：这是本系Arun Wiita博士的K08临床科学家导师研究职业发展奖的重新提交申请。加州大学旧金山分校的实验室医学博士。威塔博士在哥伦比亚大学完成了他的医学博士学位，包括在胡里奥·费尔南德斯博士的实验室完成了非常成功的单分子生物物理学研究生工作。自他在加州大学旧金山分校完成实验室医学实习以来，他一直在与吉姆·威尔斯博士一起从事血液病癌症细胞凋亡的研究。尽管进入了一个非常不同的领域，但维塔博士在两个主要项目上取得了重大进展，一个发表了，另一个提交了。他的长期目标是更详细地了解癌症细胞是如何进化和对治疗做出反应的，最终产生新的诊断工具来帮助癌症管理。K08奖项将为Wiita博士提供生物信息学、蛋白质组学和癌症信号网络方面的保护时间和额外培训，这对他作为一名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(Jim Wells)博士是治疗学和细胞死亡方面的专家，他的共同导师凯文·香农(Kevin Shannon)医学博士是恶性血液病专家，他们都有非常出色的导师记录。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博士和连接实验室医学临床和基础研究的内科科学家Scott Kogan医学博士。包括课程作业和参加研讨会和会议，威塔博士利用加州大学旧金山分校科学界的大量资源来促进他作为一名独立研究员的职业生涯。该研究提案的中心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不可治愈的侵袭性血液系统恶性肿瘤。在目标1中，威塔博士已经开始开发一种独特的管道，结合mRNA深度测序、核糖体图谱和定量蛋白质组学来监测Bortezomib诱导的骨髓瘤细胞的细胞死亡。这些研究已经揭示了对Bortezomib暴露后的翻译动力学的广泛生物学见解。在这里，他将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递的作用。在目标2中，威塔博士将使用在这条管道中获得的第一个同类数据来开发一个新的蛋白质翻译和翻译调控的定量模型。这些过程是细胞内稳态和调节的关键决定因素，也在骨髓瘤的发病机制中发挥重要作用。在目标3中，Wiita博士将使用细胞和分子生物学方法阐明骨髓瘤的耐药和反应标记物以及联合治疗靶点，基于系统水平数据的假设驱动。这些研究与NIH和NCI的任务密切相关，因为它们将极大地扩大我们对骨髓瘤的治疗效果的理解，并在未来可能对任何恶性肿瘤进行治疗。

 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.