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.

项目摘要和摘要 候选人：Sisi Chen博士是人类肿瘤学和发病机理的博士后研究助理 在纪念斯隆·克特林癌症中心（MSKCC）的计划（HOPP）。她的长期职业目标是 成为一名独立研究者，研究造血的关键调节剂的作用并确定 髓样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（Omar Abdel-Wahab）的指导下 Chen博士概述了造血性恶性肿瘤的功能性基因组学，概述了一个重点的五年职业生涯 培训计划将（1）增强科学范围和实验技能； （2）改善演示和 沟通技巧； （3）提高领导力潜力和网络； （4）准备指导未来 学员。她成立了一个咨询委员会，将为她的研究提供强大的指导， 职业发展。 Chen博士拥有一个令人兴奋的项目，与她的导师的研究完全不同， 这将形成一个可靠的平台，以在K99奖励期结束之前建立自己的研究小组。 研究：最近的研究发现LZTR1是CUL3泛素连接酶复合酶复合物的底物适配器 负责RAS GTPases的泛素介导的降解。并行，异常LZTR1剪接和 鉴定了LZTR1以及LZTR1底物（非典型RAS GTPase Rit1）中的突变 在克隆造血和髓样肿瘤中。该提议的总体目标是确定 通过正常和恶性造血的非典型RAS信号调节途径的作用 鼠建模，无偏的多词和重点生化研究的结合。我们的初步 数据表明，非典型RAS蛋白蛋白水解障碍驱动克隆造血膨胀， 导致假说，非典型的RAS GTPases及其调节剂代表重要 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 为：（1）全面鉴定造血细胞中LZTR1介导的蛋白水解的新型底物； （2）确定非经典RAS GTPase MRA在造血干细胞自我更新和 分化； （3）确定突变rit1转化造血干细胞的机制。 环境：MSKCC为受训者提供了一个卓越的学术研究环境 致力于支持他们的职业发展。 Abdel-Wahab实验室在HOPP计划中 MSKCC，专门研究基于机制的研究以推动临床翻译。这 主要导师Abdel-Wahab博士是MSK血液系统恶性肿瘤中心主任。这些 隶属关系为当前建议提供了丰富的合作，技术和科学资源。 Sisi博士 因此 要获得出色的职业发展培训，以获得独立的终身教师职位。