Understand Non-canonical RAS Signaling in Clonal Hematopoietic Disorders

了解克隆性造血疾病中的非典型 RAS 信号转导

• 批准号: 10571352
• 负责人: Sisi Chen
• 金额: $ 13.25万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10571352
• 关键词: Advisory Committees; Award; Biochemical; Biological; CUL3 gene; Cell Proliferation; Cells; Clinical; Communication; Complex; Data; Dependence; Development; Disease; Dysmyelopoietic Syndromes; Environment; Evaluation; Exhibits; Faculty; Foundations; Future; Genetic Transcription; Genomic approach; Germ-Line Mutation; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Hematologic Neoplasms; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; Human; Impairment; Individual; Institution; KRAS2 gene; Knowledge; Laboratories; Leadership; Leucine Zippers; Malignant - descriptor; Malignant Neoplasms; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Molecular; Mutation; Myelodysplastic/Myeloproliferative Disease; Myeloproliferative disease; Neurilemmoma; Noonan Syndrome; Oncogenic; Oncology; Pathogenesis; Pathway interactions; Phase; Positioning Attribute; Postdoctoral Fellow; Proliferating; Proteins; Proteolysis; Proteomics; RNA Splicing; Regulation; Research; Research Personnel; Resistance; Resources; Role; Signal Pathway; Signal Transduction; Solid; Testing; Therapeutic; Training; Ubiquitin; Ubiquitination; Up-Regulation; career; career development; clinical translation; cullin-3; cytokine; functional genomics; gain of function; hematopoietic stem cell self-renewal; human disease; improved; in vivo; loss of function; mouse model; multiple omics; mutant; neoplastic; novel; novel therapeutic intervention; programs; ras Proteins; research and development; skills; tenure track; transcriptomics; ubiquitin ligase; ubiquitin-protein ligase

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.

项目总结和摘要 候选人：陈思思博士是人类肿瘤学和发病机制的博士后研究助理 Memorial Sloan Kettering Cancer Center（MSKCC）的HOPP计划。她的长期职业目标是 成为一名独立的研究者，研究造血的关键调节因子的作用， 骨髓肿瘤的致癌驱动因素。在该领域的领导者奥马尔·阿卜杜勒-瓦哈卜博士的指导下， 在造血系统恶性肿瘤功能基因组学方面，陈博士概述了一个为期五年的职业生涯 培训计划将（1）加强科学范围和实验技能;（2）改善演示文稿， 沟通技巧;（3）提高领导潜力和网络;（4）为未来的指导做好准备 实习生她成立了一个咨询委员会，为她的研究提供强有力的指导， 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， 这将为她在K99奖结束前建立自己的研究小组提供一个坚实的平台。 研究：最近的研究发现LZTR 1作为CUL 3泛素连接酶复合物的底物衔接子 负责RAS GTP酶的泛素介导的降解。同时，异常的LZTR 1剪接和 在LZTR 1以及LZTR 1底物（一种非经典的RAS GTCRIT 1）中发现了突变， 克隆性造血和骨髓肿瘤。本提案的总体目标是确定 非经典RAS信号通路在正常和恶性造血中作用 结合鼠模型、无偏多组学和集中的生物化学研究。我们的初步 数据显示受损的非典型RAS蛋白质水解驱动克隆造血扩增， 这导致了一个假设，即非典型的RAS GTP酶及其调节因子代表了重要的 正常和肿瘤造血干细胞和祖细胞中的分子决定簇。具体目标 （1）全面鉴定造血细胞中LZTR 1介导的蛋白水解的新底物; (2)确定非经典RAS GT3/MRAS对造血干细胞自我更新的作用， （3）确定突变RIT 1转化造血干细胞的机制。 环境：MSKCC为学员提供了一个特殊的学术研究环境， 支持他们的职业发展。Abdel-Wahab实验室是HOPP计划的一部分， MSKCC是一个专门从事基于机制的研究以推进临床翻译的部门。的 Abdel-Wahab博士是MSK血液肿瘤中心的主任。这些 各附属机构为目前的提案提供了丰富的协作、技术和科学资源。西西博士 因此，Chen也处于执行本文所述研究的最佳机构环境中 接受优秀的职业发展培训，以获得独立的终身教职。