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：
8260490
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 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8260490
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 graduate student in vivo inhibitor/antagonist instructor medical schools mouse model next generation 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. PUBLIC HEALTH RELEVANCE: Project Narrative We propose that tumors bypass and suppress T cell immune responses by turning off genes within T cells using a process called DNA methylation. This project seeks to identify T cell genes turned off by tumors due to DNA methylation and test whether blocking DNA methylation is able to enhance immune responses against tumors. Identifying a role for DNA methylation in preventing anti-tumor immunity suggests that drugs that block DNA methylation will enhance treatment of cancer with immunotherapy.

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小儿肿瘤学系的第二年讲师。在此提案中，我旨在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，以使我能够分析淋巴细胞中DNA甲基化的全基因组模式，尤其是在肿瘤抗原激活的T细胞中。我的直接目标是检验以下假设：TNA激活基因的DNA甲基化和沉默导致对癌症的免疫反应无效。我的长期目标是利用该提案来建立独立的研究线，该研究可能会转化为儿科肿瘤科中患者的临床相关免疫疗法。研究我的先前努力已经确定了DNA甲基转移酶3A（DNMT3A）在激活后T细胞中细胞因子基因的从头催化剂DNA甲基化中的关键作用。在此提案中，我将检验以下假设：这种甲基化有助于无效的抗肿瘤免疫力。我将使用一个强大的小鼠模型，其T细胞缺乏DNMT3A来通过比较全基因组甲基化分析中暴露于肿瘤和激活的T细胞来鉴定DNA甲基化的未引起的靶标。我将确定缺乏这种甲基化是否是DNMT3A KO T细胞更好地拒绝肿瘤的观察到的能力，并且我将测试治疗DNMT抑制剂是否可以达到相似的作用。这样的发现将确定DNMT抑制作用是增强抗肿瘤免疫力并有可能导致更有效的癌症疫苗策略的新型手段。环境：我的建议将在乔纳森·鲍威尔（Jonathan Powell）博士的持续指导下进行，他是T细胞激活，效应子分化和耐受性生物学的主要研究员。他领导了一个高产的实验室，并成功指导了四名研究生和三名博士后研究员。通过与下一代测序中心主任Srinivasan Yegnasubramanian博士的合作，我将在下一代测序中应用最新的技术进步，以测量全球基因组DNA甲基化模式。生物技术教育中心和计算基因组学中心将为生物信息学的正规教育提供课程。这些元素结合在一起，为我提供了坚实的基础，以发展独立医师科学家的职业。公共卫生相关性：项目叙述我们建议肿瘤通过使用称为DNA甲基化的过程在T细胞中关闭基因来绕过和抑制T细胞免疫反应。该项目旨在鉴定由于DNA甲基化而被肿瘤关闭的T细胞基因，并测试阻断DNA甲基化是否能够增强针对肿瘤的免疫反应。确定DNA甲基化在预防抗肿瘤免疫中的作用表明，阻断DNA甲基化的药物将通过免疫疗法增强癌症的治疗。