Inhibition of DNA methylation to prevent tumor-induced immune tolerance

抑制DNA甲基化以防止肿瘤诱导的免疫耐受

基本信息

批准号：
8446400
负责人：
CHRISTOPHER J GAMPER
金额：
$ 13.47万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8446400
关键词：
Antigens Bioinformatics Biology Biotechnology Bypass Cancer Vaccines Cell Cycle Chromatin Collaborations Complement Cyclin A Cytokine Gene DNA Methylation DNA Methylation Inhibition DNA Methyltransferase DNA Modification Methylases DNA Sequence DNA Sequence Rearrangement Data Education Educational Curriculum Elements Environment Epigenetic Process Exposure to Foundations Gene Expression Gene Silencing Genes Genomics Goals Immune Tolerance Immune response Immunology Immunotherapy Interferons Interruption Laboratories Lead Lymphocyte Lymphoma Malignant Neoplasms Measurement Measures Mediating Mentors Mentorship Methylation Modeling Mus Patients Pattern Pediatric Oncology Pharmaceutical Preparations Phenotype Physicians Play Postdoctoral Fellow Process Publishing Recruitment Activity Regulation Regulatory T-Lymphocyte Research Research Personnel Resistance Role Scientist Solid T-Cell Activation T-Lymphocyte Testing Time Translating Tumor Antigens Tumor Immunity Universities Vaccines abstracting anergy base bisulfite cancer therapy career clinically relevant cytokine daughter cell genome wide methylation genome-wide graduate student in vivo inhibitor/antagonist instructor medical schools mouse model next generation sequencing novel novel strategies prevent promoter public health relevance response transcription factor tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Project Summary/Abstract Candidate I am a second year Instructor in the Division of Pediatric Oncology at the Johns Hopkins University School of Medicine. In this proposal I aim to complement ongoing research in immunology with a formal bioinformatics education to permit me to analyze genome-wide patterns of DNA methylation in lymphocytes, in particular in T cells that have been activated by tumor antigen. My immediate goals are to test the hypothesis that DNA methylation and silencing of T cell activation genes contributes to the ineffective immune responses against cancer. My long-term goal is to utilize this proposal to establish an independent line of research that may be translated into clinically relevant immunotherapy for patients in the Division of Pediatric Oncology. Research My prior efforts have identified a critical role for DNA Methyltransferase 3a (DNMT3a) in catalyzing de novo DNA methylation of cytokine genes in T cells following activation. In this proposal I will test the hypothesis that such methylation contributes to ineffective anti-tumor immunity. I will use a robust model of mice whose T cells lack DNMT3a to identify unappreciated targets of DNA methylation by comparing tumor exposed and activated T cells in an genome-wide methylation analysis. I will determine whether lack of such methylation underlies the observed ability of DNMT3a KO T cells to better reject tumors, and I will test whether treatment DNMT inhibitors can achieve a similar effect. Such a finding would identify DNMT inhibition as a novel means of enhancing anti-tumor immunity and potentially lead to more effective cancer vaccine strategies. Environment: My proposal will be carried out under the ongoing mentorship of Dr. Jonathan Powell, a leading researcher in the biology of T cell activation, effector differentiation, and tolerance. He leads a highly productive laboratory and has successfully mentored four graduate students and three postdoctoral fellows. Through collaboration with Dr. Srinivasan Yegnasubramanian, Director of the Next Generation Sequencing Center, I will apply the latest technological advances in next generation sequencing to the measurement of global patterns of genomic DNA methylation. The Center for Biotechnology Education and the Center for Computational Genomics will provide a curriculum for formal education in bioinformatics. These elements combine to provide me with a solid foundation to develop a career as an independent physician-scientist.

描述（由申请人提供）：项目摘要/摘要候选人我是约翰霍普金斯大学医学院儿科肿瘤科的二年级讲师。在本提案中，我的目标是通过正式的生物信息学教育来补充正在进行的免疫学研究，使我能够分析淋巴细胞中 DNA 甲基化的全基因组模式，特别是在被肿瘤抗原激活的 T 细胞中。我的近期目标是检验 DNA 甲基化和 T 细胞激活基因沉默会导致针对癌症的无效免疫反应的假设。我的长期目标是利用这一提案建立一条独立的研究路线，该研究路线可以转化为针对儿科肿瘤科患者的临床相关免疫疗法。研究我之前的工作已经确定了 DNA 甲基转移酶 3a (DNMT3a) 在催化 T 细胞激活后细胞因子基因从头 DNA 甲基化中的关键作用。在这个提案中，我将测试这样的假设：这种甲基化会导致无效的抗肿瘤免疫。我将使用 T 细胞缺乏 DNMT3a 的稳健小鼠模型，通过在全基因组甲基化分析中比较暴露于肿瘤的 T 细胞和激活的 T 细胞，来识别未被识别的 DNA 甲基化靶标。我将确定缺乏这种甲基化是否是观察到的 DNMT3a KO T 细胞更好地排斥肿瘤的能力的基础，并且我将测试 DNMT 抑制剂治疗是否可以达到类似的效果。这一发现将确定 DNMT 抑制是增强抗肿瘤免疫力的一种新方法，并有可能导致更有效的癌症疫苗策略。环境：我的提案将在 Jonathan Powell 博士的持续指导下进行，他是 T 细胞激活、效应分化和耐受生物学领域的领先研究员。他领导着一个高产的实验室，并成功指导了四名研究生和三名博士后。通过与下一代测序中心主任 Srinivasan Yegnasubramanian 博士的合作，我将应用下一代测序的最新技术进步来测量基因组 DNA 甲基化的全局模式。生物技术教育中心和计算基因组学中心将为生物信息学正规教育提供课程。这些要素相结合，为我发展成为一名独立的医师科学家的职业生涯奠定了坚实的基础。