Harnessing the repetitive genome for cancer immunotherapy

利用重复基因组进行癌症免疫治疗

• 批准号: 10664127
• 负责人: Gabriel K. Griffin
• 金额: $ 26.88万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664127
• 关键词: 3-Dimensional; Advisory Committees; Antigens; Area; Automobile Driving; Binding; Biological Markers; Biological Response Modifiers; Burn injury; CTLA4 gene; Cancer Biology; Cell division; Chromatin; Chromatin Remodeling Factor; Communication; DNA Transposable Elements; Dana-Farber Cancer Institute; Data; Detection; Development; Elements; Enhancers; Epigenetic Process; Evolution; Faculty; Future; Gene Activation; Genes; Genetic Transcription; Genome; Genomics; Goals; Hematopathology; Hospitals; Human; Immune; Immune Evasion; Immunotherapy; International; Knock-out; Knowledge; Laboratories; Leadership; Lewis Lung Carcinoma; Lewis lung carcinoma cell; Malignant Neoplasms; Maps; Mediating; Mentors; Modeling; Mus; Nature; PAX3 gene; Pathology; Pathway interactions; Patients; Physicians; Play; Proteins; Regulation; Research; Role; SETDB1 gene; Scientist; Signal Transduction; System; Testing; Training; Training Programs; Transcriptional Activation; Transcriptional Silencer Elements; Tumor Immunity; Woman; Work; cancer cell; cancer genome; cancer immunotherapy; cancer type; career; career development; clinical training; derepression; epigenetic regulation; epigenetic silencing; epigenetic therapy; epigenomics; experience; immune activation; immune checkpoint blockade; immunoregulation; in vivo; insight; loss of function; lung cancer cell; medical schools; meetings; melanocyte; melanoma; neoplastic cell; novel; professor; programmed cell death protein 1; programs; promoter; recruit; response; restoration; skills; transcription factor; tumor; tumor immunology

PROJECT SUMMARY This KOS proposal describes a five-year career development training program in cancer epigenetics and tumor immunology. Dr. Gabriel Griffin has completed clinical training in Hematopathology at Brigham and Women's Hospital and Harvard Medical School (HMS), and will embark on this research program with the goal of training for an independent laboratory-based career investigating basic mechanisms of immune regulation in cancer. In this training program, Dr Griffin will develop further expertise in the study of transposable elements and tumor immunity. and acquire new skills in the areas of genome topology. including the functional analysis of enhancer-promoter loops which will critically enable his future studies. His mentor, Dr. Bradley Bernstein (Chair of Cancer Biology at Dana-Farber Cancer Institute, Professor of Pathology at HMS, Director of the Epigenomics Program at the Broad Institute of MIT and Harvard) is an international leader in the field of cancer epigenomics with an excellent track record in mentoring trainees, including as independent laboratory-based faculty at major academic centers. Dr. Griffin has also assembled an Advisory Committee with complementary expertise in transposable elements (Dr. Burns), tumor immunology (Dr. Sharpe), and computational genomics (Dr. Van Allen), and extensive experience in mentoring physician-scientists to independent careers. Dr. Griffin will further supplement his training with didactic courses to deepen his scientific knowledge, leadership, and communication, and will regularly present his work at national and international meetings. The primary objective of Dr. Griffin's proposed research is to study epigenetic mechanisms of transposable element (TE) silencing and immune regulation in cancer cells. Dr. Griffin provides preliminary data indicating that lineage-specific re g PAX3 in melanoma} and conserved (e.g. CTCF) transcription factors (TFs} drive TE and immune gene activation in cancer cells following perturbation of SETDB1. a novel immunotherapy target identified in Dr Griffin's prior work (Griffin et al., Nature 2021). This proposal will examine the specific regulatory mechanisms that drive transcriptional responses in melanoma following SETDB1 loss, and will test the hypothesis that activation of latent TEs triggers consequent changes in regulatory circuitry and locus topology to drive immune activation. These studies will uncover fundamental mechanisms of epigenetic regulation of TEs and immune loci in melanoma. with broad potential applicability to other cancer types and the fields of of cancer epigenetics. tumor immunology. and immunotherapy.

项目总结 这份KOS提案描述了一项为期五年的癌症表观遗传学和肿瘤免疫学职业发展培训计划。加布里埃尔·格里芬博士已经在布里格姆妇女医院和哈佛医学院(HMS)完成了血液病理学的临床培训，他将开始这项研究计划，目标是为研究癌症免疫调节基本机制的独立实验室职业生涯进行培训。在这项培训计划中，格里芬博士将在转座因子和肿瘤免疫研究方面发展更多的专业知识。并获得基因组拓扑学领域的新技能。包括对增强子-启动子环的功能分析，这将对他未来的研究至关重要。他的导师布拉德利·伯恩斯坦博士(Dana-Farber癌症研究所癌症生物学主席、HMS病理学教授、麻省理工学院博德研究所和哈佛大学表观基因组学项目主任)是癌症表观基因组学领域的国际领导者，在指导学员方面有着出色的记录，包括作为主要学术中心的独立实验室教师。格里芬博士还组建了一个咨询委员会，在转座基因(Burns博士)、肿瘤免疫学(Sharpe博士)和计算基因组学(Van Allen博士)方面具有互补的专业知识，并在指导内科科学家独立职业方面拥有丰富的经验。格里芬博士将通过教学课程进一步补充他的培训，以加深他的科学知识、领导力和沟通能力，并将定期在国内和国际会议上介绍他的工作。格里芬博士提出的研究的主要目标是研究癌细胞中转座元件(TE)沉默和免疫调节的表观遗传机制。Griffin博士提供的初步数据表明，在SETDB1的干扰之后，谱系特异性的reg PAX3在黑色素瘤中)和保守的(例如CTCF)转录因子(TF)推动癌细胞中TE和免疫基因的激活。Griffin博士先前工作中确定的一种新的免疫治疗靶点(Griffin等人，《自然》2021)。这项提案将研究在SETDB1丢失后驱动黑色素瘤转录反应的特定调控机制，并将检验以下假设：潜在TES的激活会触发调控电路和基因座拓扑的相应变化，从而驱动免疫激活。这些研究将揭示黑色素瘤中TES和免疫位点的表观遗传调节的基本机制。具有广泛的潜在适用性，可应用于其他癌症类型和癌症表观遗传学领域。肿瘤免疫学。和免疫疗法。