Analysis and Therapeutic Targeting Non-proteolytic Protein Ubiquitination in Diffuse Large B Cell Lymphoma

弥漫性大 B 细胞淋巴瘤中非蛋白水解蛋白泛素化的分析和治疗

• 批准号: 9339622
• 负责人: Yibin Yang
• 金额: $ 19.46万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339622
• 关键词: Address; Apoptosis Inhibitor; Applications Grants; B-Cell Lymphomas; B-Lymphocytes; Biochemical; Biological; CRISPR/Cas technology; Cell Proliferation; Cell Survival; Cells; Chronic; Clinical; Clinical Trials; Complex; Data; Disease; Exhibits; Family; Foundations; Future; Gene Expression Profiling; Genetic; Goals; Hematologic Neoplasms; Human; Immune; Immune signaling; Immunologics; Knock-out; Knowledge; Link; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediating; Mus; Oncogenic; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Physiological; Polyubiquitin; Postdoctoral Fellow; Proteins; Publications; Receptor Signaling; Receptors, Antigen, B-Cell; Recruitment Activity; Regulatory Pathway; Research; Role; Scientist; Signal Pathway; Signal Transduction; Signal Transduction Pathway; System; Testing; Therapeutic; Toxic effect; Ubiquitin; Ubiquitination; Work; Xenograft Model; Yang; cancer type; career; drug development; experience; human disease; in vivo Model; interdisciplinary approach; interest; large cell Diffuse non-Hodgkin' s lymphoma; mimetics; multidisciplinary; neoplastic cell; novel therapeutics; post-doctoral training; protein function; public health relevance; response; skills; small molecule; therapeutic target; treatment strategy; tumor; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): My doctoral and post-doctoral training have collectively focused on using multidisciplinary genetic, biochemical and immunological approaches to dissect the function of protein ubiquitination in signaling and diseases. With the experience, knowledge and skills I gained from my doctoral and post-doctoral training, I am now prepared to start as an independent scientist to continue my research of signal transduction pathways in hematologic malignancies, with a particular interested in ubiquitin-mediated signaling and immune regulatory pathways in lymphoma pathogenesis. My future independent research will build upon my post-doctoral studies of the critical role of both the proteolytic and nonproteolytic protein ubiquitination system in lymphoma pathogenesis. My current objective is to apply multidisciplinary approaches to investigate the role of protein ubiquitination systems in the pathogenesis of lymphoid malignancies. The proposed K22 proposal in this application directly builds upon my post-doctoral training, and the publication/results from this proposal will serve as a foundation of my future grant application. My long-term career goal/objective is to direct new treatment strategies for human disease like lymphoma by targeting protein ubiquitination system. I believe my research will broaden our fundamental understanding of immune regulatory mechanisms in lymphomagenesis and open up new avenues for drug development. The proposed study entitled "Analysis and Therapeutic Targeting Non-proteolytic Protein Ubiquitination in Diffuse Large B Cell Lymphoma" will address the importance of cIAP1/2 E3 ligases in the pathogenesis of Activated B Cell-like subtype of Diffuse Large B Cell Lymphoma (ABC DLBCL), and that SMAC mimetics could be a novel therapeutic strategy in this disease. In this study, the requirement of cIAP1/2 their enzymatic activities in chronic active B Cell Receptor (BCR) signaling pathway mediated NF-B activation will be defined by CRISPR/CAS9 genetic knockout approach. Biochemically, the detailed mechanism of how cIAP1/2 E3 ligases mediate BCR signaling will be established. Lastly, the therapeutic potential of SMAC mimetic birinapant in ABC DLBCL will be exploit in human lymphoma lines and in various DLBCL mice xenograft models in vivo. Moreover, a high-throughput small molecule screen will be used to identify other drugs that exhibit synergistic toxicity for ABC DLBCL cells when combined with birinapant, to increase the response rates and durability.

 描述（由申请人提供）：我的博士和博士后培训集中在使用多学科遗传学，生物化学和免疫学方法来剖析蛋白质泛素化在信号传导和疾病中的功能。凭借我在博士和博士后培训中获得的经验，知识和技能，我现在准备作为一名独立的科学家开始继续我对血液恶性肿瘤信号转导途径的研究，特别是对淋巴瘤发病机制中的泛素介导的信号传导和免疫调节途径感兴趣。我未来的独立研究将建立在我的博士后研究的蛋白水解和非蛋白水解蛋白泛素化系统在淋巴瘤发病机制中的关键作用。我目前的目标是应用多学科的方法来研究蛋白质泛素化系统在淋巴恶性肿瘤发病机制中的作用。本申请中提出的K22提案直接建立在我的博士后培训基础上，该提案的出版物/结果将 作为我未来申请资助的基础我的长期职业目标是通过靶向蛋白质泛素化系统指导人类疾病如淋巴瘤的新治疗策略。我相信我的研究将拓宽我们对淋巴瘤发生中免疫调节机制的基本理解，并为药物开发开辟新的途径。拟定的题为“弥漫性大B细胞淋巴瘤中非蛋白水解蛋白泛素化的分析和治疗靶向”的研究将阐述cIAP 1/2 E3连接酶在弥漫性大B细胞淋巴瘤的活化B细胞样亚型（ABC DLBCL）发病机制中的重要性，以及SMAC模拟物可能是该疾病的新型治疗策略。在本研究中，将通过CRISPR/CAS 9基因敲除方法来定义慢性活性B细胞受体（BCR）信号通路介导的NF-κ B B活化中cIAP 1/2及其酶活性的需求。在生物化学上，cIAP 1/2 E3连接酶如何介导BCR信号传导的详细机制将被建立。最后，SMAC模拟物birinapant在ABC DLBCL中的治疗潜力将在人淋巴瘤细胞系和各种DLBCL小鼠异种移植物模型中体内开发。此外，高通量小分子筛选将用于鉴定当与birinapant组合时对ABC DLBCL细胞表现出协同毒性的其他药物，以增加响应率和耐久性。