Targeting nutrient-sensing pathways in cancer

 描述（由申请人提供）：本次NCI过渡职业发展奖（K22）的候选人是Michael Lazarus，博士，他是加州大学旧金山分校弗朗西斯科Kevan Shokat教授实验室的博士后研究员。Lazarus博士在结构生物学和生物化学方面有很强的背景。但在博士后和K22奖期间，他一直在寻求获得蛋白质组学、细胞生物学和核糖体分析方面的额外经验。在奖励期结束时，Lazarus博士将拥有一套全面而令人兴奋的技能，他将能够在与营养信号相关的癌症生物学方面进行尖端研究。他的长期目标是在一所研究型大学拥有自己的实验室，专注于研究细胞对营养变化的反应机制，这些机制如何在癌症中改变，以及最终如何将它们用于新的治疗策略。这项研究计划的重点是两种不寻常的酶，它们调节细胞对饥饿的反应。一种是称为延伸因子-2激酶（eEF 2K）的蛋白质，其功能是调节细胞对营养剥夺的反应。该激酶属于称为α激酶的非典型激酶家族;它具有非典型序列，并且没有从用于研究常规蛋白激酶的工具的最新发展中受益。eEF 2K已被证明对肿瘤存活很重要，因为它使癌细胞对营养变化产生抗性，但其机制尚不清楚。在这项提案中，Lazarus博士试图确定eEF 2K的新底物，并了解翻译的调节如何使癌细胞适应营养缺乏。通过确定哪些转录本最受eEF 2K活性的影响，将出现对翻译调控的新理解。另一种酶是一种名为ULK 1的激酶，它可以启动细胞中的自噬，这是一个细胞在营养不足时可以降解细胞成分以获取能量的过程。Lazarus博士将开发ULK 1的第一个细胞抑制剂，并探测激酶在癌症中的功能。通过开发研究这两种酶的工具，Lazarus博士将在研究癌症中的营养信号方面有一个坚实的计划。Lazarus博士组建了一支令人印象深刻的科学家团队，帮助他解决这些具有挑战性的问题，并学习新技能，以完成培训并过渡到独立调查员。他目前的导师是Kevan Shokat，他是识别激酶底物、开发选择性激酶抑制剂以及使用化学工具解开癌症中复杂信号通路的世界领导者。Lazarus博士一直在Shokat教授的实验室工作，并将开发工具来了解eEF 2K和ULK 1。在Shokat教授的实验室里，Michael一直在学习底物识别技术以及有机合成技术，以制造新的抑制剂。此外，Lazarus博士一直在接受两位领先科学家的培训，他们是UCSF Shokat教授的长期合作者。William韦斯教授是神经母细胞瘤模型方面的世界级专家，他将培训Lazarus博士研究eEF 2K在癌细胞系中的作用，在癌细胞系中，激酶与患者预后密切相关。通过学习如何在相关细胞系中研究激酶及其底物，Lazarus博士正在获得基础细胞生物学技术的经验，并学习eEF 2K在相关疾病模型中功能的新途径，这将成为Lazarus博士独立研究的一部分。Lazarus博士还受益于与Davide Ruggero教授的合作，他是翻译调控和核糖体分析方面的领先专家。通过与Ruggero教授合作，Lazarus博士将学习核糖体分析和翻译的生化分析技术。韦斯教授和鲁杰罗教授都位于加州大学旧金山分校的校园，并一直与博士Lazarus和Shokat教授经常会面，为这个合作和多学科项目提供指导。Lazarus博士一直与韦斯教授和Ruggero教授的实验室成员密切合作，学习新技术并回答有关他的项目的问题。拉扎勒斯博士作为一名科学家的培训的一个关键组成部分，因为他的导师正在与几十名具有不同专业知识的UCSF教职员工合作。这些非正式的互动和建议将是宝贵的资源。Lazarus将参加UCSF的关键研讨会，这将补充他的实验室培训与专业发展。总之，由于UCSF严格的培训计划和协作环境，Lazarus博士将处于独特的地位，能够对eEF 2K和ULK 1做出新的发现，并为强大的独立学术生涯做好准备。

 DESCRIPTION (provided by applicant): The candidate for this NCI Transition Career Development Award (K22) is Michael Lazarus, Ph.D., a postdoctoral researcher in the lab of Professor Kevan Shokat at the University of California, San Francisco. Dr. Lazarus has a strong background in structural biology and biochemistry from his Ph.D. but has sought to gain additional experience in proteomics, cell biology, and ribosomal profiling in his postdoctoral and K22 award period. At the end of the award period, Dr. Lazarus will have a well-rounded and exciting set of skills with which he will be able to carry out cutting edge research in cancer biology related to nutrient signaling. His long-term goal is to have his own lab at a research university focused on studying the mechanisms by which cells respond to nutrient changes, how these mechanisms can be altered in cancer, and finally how they can be exploited for novel therapeutic strategies. The focus of this research proposal centers around two unusual enzymes that regulate cellular responses to starvation. One is a protein called elongation factor-2 kinase (eEF2K) which functions to regulate translation in cells in response to nutrient deprivation. The kinase belongs to an atypical family of kinases called alpha kinases; it has a non-canonical sequence and has not benefitted from the recent development of tools used to study conventional protein kinases. eEF2K has been shown to be important for tumor survival by rendering cancer cells resistant to nutrient changes, but the mechanisms by which it does this are unclear. In this proposal, Dr. Lazarus seeks to identify novel substrates of eEF2K and understand how regulation of translation allows cancer cells to adapt to nutrient deprivation. By determining which transcripts are most affected by eEF2K activity, a new understanding of translation regulation will emerge. The other enzyme is a kinase called ULK1 that initiates autophagy in cells, a process whereby cells can degrade cellular components for energy when nutrients are low. Dr. Lazarus will develop the first cellular inhibitors of ULK1 and probe the kinase's function in cancer. By developing tools to study these two enzymes, Dr. Lazarus will have a solid program in studying nutrient signaling in cancer. Dr. Lazarus has assembled an impressive team of scientists to help him tackle these challenging questions and learn new skills to complete his training and transition into an independent investigator. His current mentor is Kevan Shokat, a world leader in indentifying substrates of kinases, developing selective kinase inhibitors, and using chemical tools to unravel complex signaling pathways in cancer. Dr. Lazarus has been working in Professor Shokat's laboratory, and will develop tools to understand eEF2K and ULK1. In Professor Shokat's lab, Michael has been learning techniques of substrate identification as well as organic synthesis for making new inhibitors. In addition, Dr Lazarus has been receiving training from two leading scientists who are longtime collaborators with Professor Shokat at UCSF. Professor William Weiss is a world expert on neuroblastoma models and will train Dr. Lazarus to investigate the role of eEF2K in cancer cell lines where the kinase has been strongly linked to patient prognosis. By learning how to investigate the kinase and its substrates in relevant cell lines, Dr. Lazarus is gaining experience in fundamental cell biology techniques as well as learning new avenues of eEF2K function in relevant disease models that will become part of Dr. Lazarus's independent research. Dr. Lazarus is also benefiting from working with Professor Davide Ruggero, who is a leading expert on translation regulation and ribosomal profiling. By working with Professor Ruggero, Dr. Lazarus will learn techniques in ribosomal profiling and biochemical analysis of translation. Both Professor Weiss and Professor Ruggero are located at the UCSF campus and have been meeting frequently with Dr. Lazarus and Professor Shokat to provide guidance on this collaborative and multi-disciplinary project. Dr. Lazarus has been working closely with members of Professor Weiss's and Professor Ruggero's labs to learn new techniques and answer questions about his project. This rich environment at UCSF will be a key component of Dr. Lazarus's training as a scientist, since his mentor has ongoing collaborations with dozens of faculty members at UCSF with different expertises. These more informal interactions and advice will be an invaluable resource. In addition, Dr. Lazarus will attend key workshops UCSF that will supplement his laboratory training with professional development. In summary, because of this rigorous training plan and collaborative environment at UCSF, Dr. Lazarus will be uniquely positioned to make new discoveries about eEF2K and ULK1 and also be ready for a strong independent academic career.