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于使用多学科的遗传学、生化和免疫学方法来剖析蛋白质泛素化在信号和疾病中的功能。凭借我在博士和博士后培训中获得的经验、知识和技能，我现在准备开始作为一名独立科学家继续我在血液系统恶性肿瘤中的信号转导途径的研究，特别是对淋巴瘤发病机制中泛素介导的信号和免疫调节途径的兴趣。我未来的独立研究将建立在我的博士后研究基础上，即蛋白水解性和非蛋白水解性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方法来研究蛋白质泛素化系统在淋巴系统恶性肿瘤发病机制中的作用。本申请中建议的K22提案直接建立在我博士后培训的基础上，该提案的发布/结果将 作为我未来拨款申请的基础。我的长期职业目标是通过靶向蛋白质泛素化系统来指导人类疾病(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。这项名为“弥漫性大B细胞淋巴瘤中非蛋白水解性蛋白泛素化的分析和治疗”的研究将阐述cIAP1/2 E3连接酶在活化的B细胞样弥漫性大B细胞淋巴瘤(ABC DLBCL)发病机制中的重要性，Smac类似物可能成为该疾病的一种新的治疗策略。本研究将通过CRISPR/9基因敲除的方法确定慢性活性B细胞受体信号通路中CIAP1/2的酶活性所需的条件。在生物化学方面，cIAP1/2 E3连接酶如何介导BCR信号转导的详细机制将被建立。最后，Smac模拟物在ABC DLBCL中的治疗潜力将被开发在人淋巴瘤细胞系和各种DLBCL小鼠体内移植模型中。此外，高通量小分子筛选将被用来识别当与Birinapant联合使用时对ABC DLBCL细胞显示协同毒性的其他药物，以提高应答率和耐受性。