Understand Non-canonical RAS Signaling in Clonal Hematopoietic Disorders

项目摘要和摘要 候选人：陈思思博士是人类肿瘤学和病理学的博士后研究助理 在纪念斯隆·凯特琳癌症中心(MSKCC)的项目(Hopp)。她的长期职业目标是 成为一名独立的调查者，研究造血的关键调节因素的作用，并确定 髓系肿瘤的致癌驱动因素。在该领域的领军人物奥马尔·阿卜杜勒-瓦哈布博士的指导下 在血液系统恶性肿瘤的功能基因组学方面，陈博士勾勒出了他专注于五年的职业生涯 培训计划，将(1)加强科学范围和实验技能；(2)改进陈述和 沟通技能；(3)增强领导潜力和网络；以及(4)为未来的指导做好准备 实习生。她已经建立了一个咨询委员会，将为她的研究和 职业发展。陈博士有一个非常令人兴奋的项目，与她导师的研究截然不同。 这将形成一个坚实的平台，在K99奖期结束时建立她自己的研究小组。 研究：最近的研究发现LZTR1是CUL3泛素连接酶复合体的底物接头 负责泛素介导的RAS GTP酶的降解。同时，异常的LZTR1剪接和 LZTR1和LZTR1底物，一种非规范的RAS GTP酶RIT1，被鉴定为突变 在克隆性造血和髓系肿瘤中。这项提案的首要目标是确定 非典型RAS信号调节通路在正常和恶性造血中的作用 结合了小鼠建模、无偏见的多组学和重点生化研究。我们的预赛 数据显示，受损的非典型RAS蛋白分解推动克隆性造血扩张， 从而导致假设非规范的RAS GTP酶及其调节因子代表重要的 正常和肿瘤造血干细胞和祖细胞中的分子决定因素。具体目标 主要内容有：(1)全面鉴定LZTR1介导的造血细胞蛋白分解的新底物； (2)确定非规范RAS GTP酶MRAs在造血干细胞自我更新和 (3)确定突变的RIT1转化造血干细胞的机制。 环境：MSKCC为学员提供卓越的学术研究环境和强大的 承诺支持他们的职业发展。Abdel-Wahab实验室在霍普计划中，网址为 MSKCC是一个专门从事以机制为基础的研究以推进临床翻译的部门。这个 主要导师Abdel-Wahab博士是MSK血液恶性肿瘤中心的主任。这些 伙伴关系为当前的提案提供了丰富的协作、技术和科学资源。塞西博士 因此，陈也处于执行本文概述的研究的最佳制度环境中 至于接受出色的职业发展培训，以获得独立的终身教职。

PROJECT SUMMARY AND ABSTRACT CANDIDATE: Dr. Sisi Chen is a postdoctoral research associate in the Human Oncology and Pathogenesis Program (HOPP) at the Memorial Sloan Kettering Cancer Center (MSKCC). Her long-term career goal is to become an independent investigator, studying the role of critical regulators of hematopoiesis and identifying oncogenic drivers of myeloid neoplasms. Under the mentorship of Dr. Omar Abdel-Wahab, a leader in the field of functional genomics of hematopoietic malignancies, Dr. Chen has outlined a focused five-year career training plan that will (1) bolster scientific scope and experimental skillsets; (2) improve presentation and communication skills; (3) enhance leadership potential and networking; and (4) prepare for mentoring future trainees. She has established an advisory committee that will provide robust mentoring for her research and career development. Dr. Chen has a highly exciting project that is sufficiently distinct from her mentor's research, and that will form a solid platform to establish her own research group by the end of the K99 Award period. RESEARCH: Recent studies discovered LZTR1 as a substrate adaptor for a CUL3 ubiquitin ligase complex responsible for ubiquitin-mediated degradation of RAS GTPases. In parallel, aberrant LZTR1 splicing and mutations in LZTR1 as well as the LZTR1 substrate, a non-canonical RAS GTPase RIT1, were identified in clonal hematopoiesis and myeloid neoplasms. The overarching goal of this proposal is to determine the role of non-canonical RAS signaling regulation pathway in normal and malignant hematopoiesis through a combination of murine modeling, unbiased multi-omics, and focused biochemical studies. Our preliminary data shows that impaired non-canonical RAS protein proteolysis drives clonal hematopoietic expansion, leading to the hypothesis that non-canonical RAS GTPases and their regulator represent important molecular determinants in normal and neoplastic hematopoietic stem and progenitor cells. The Specific Aims are: (1) Comprehensively Identify novel substrates for LZTR1-mediated proteolysis in hematopoietic cells; (2) Determine the role of non-canonical RAS GTPase MRAS on hematopoietic stem cell self-renewal and differentiation; and (3) Identify the mechanisms by which mutant RIT1 transforms hematopoietic stem cells. ENVIRONMENT: MSKCC provides trainees an exceptional academic research environment with a strong commitment to support their career development. The Abdel-Wahab laboratory is in the HOPP program at MSKCC, a department that specializes in mechanism-based research to advance clinical translation. The primary mentor Dr. Abdel-Wahab is the Director of the MSK Center for Hematologic Malignancies. These affiliations provide a rich set of collaboratives, technical and scientific resources for the current proposal. Dr. Sisi Chen is therefore positioned at the best institutional environment to execute the research outlined here, as well as to receive outstanding career development training to obtain an independent tenure-track faculty position.