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.

项目概要 该 KOS 提案描述了癌症表观遗传学和肿瘤免疫学领域的为期五年的职业发展培训计划。 Gabriel Griffin 博士已在布莱根妇女医院和哈佛医学院 (HMS) 完成了血液病理学临床培训，并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提供培训。在本次培训计划中，格里芬博士将进一步发展转座元件和肿瘤免疫研究方面的专业知识。并获得基因组拓扑领域的新技能。包括增强子-启动子环的功能分析，这对于他未来的研究至关重要。他的导师 Bradley Bernstein 博士（达纳-法伯癌症研究所癌症生物学主席、哈佛医学院病理学教授、麻省理工学院和哈佛大学博德研究所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，在指导学员方面拥有出色的记录，包括在主要学术中心担任独立实验室教师。格里芬博士还组建了一个咨询委员会，该委员会在转座元件（伯恩斯博士）、肿瘤免疫学（夏普博士）和计算基因组学（范艾伦博士）方面具有互补的专业知识，并且在指导医师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展示他的工作。 Griffin 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 博士提供了初步数据，表明黑色素瘤中的谱系特异性 re g PAX3} 和保守的（例如 CTCF）转录因子 (TFs} 在 SETDB1 扰动后驱动癌细胞中的 TE 和免疫基因激活。Griffin 博士之前的工作中发现了一个新的免疫治疗靶点（Griffin 等人，Nature 2021）。该提案将研究具体的调控机制 SETDB1 丢失后驱动黑色素瘤中的转录反应，并将检验潜在 TE 的激活会引发调节电路和基因座拓扑的后续变化以驱动免疫激活的假设。这些研究将揭示黑色素瘤中 TE 和免疫位点表观遗传调控的基本机制。对其他癌症类型和癌症表观遗传学领域具有广泛的潜在适用性。肿瘤免疫学。和 免疫疗法。