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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（通过应用程序证明）：我的博士学位和博士培训集体使用多学科，生物化学和免疫学方法，用于蛋白质无处不在的信号传导和疾病的功能。，在血液学中，我对信号转导的病理学的研究具有特定的对泛素介导的信号传导和免疫调节途径的感兴趣。在淋巴瘤中。作为我的长期职业目标/目标，是针对人类疾病的新信任，以靶向蛋白质的泛素化系统。 - 弥漫性大B细胞淋巴瘤中的蛋白质促促尿液”将解决CIAP1/2 E3 Ligauss在活化B细胞的发病机理中的重要性。在ABC DLBCL中，Will Will Will Will Will Will Will Will Will Will Will Will Will Will Will Will Will Will Will Will Will Will will在体内的各种DLBCL胶束中都将被剥削。