DNA Damage and Immunogenicity in Ewing Sarcoma

尤文肉瘤中的 DNA 损伤和免疫原性

基本信息

批准号：
10213196
负责人：
Kelly Bailey
金额：
$ 15.3万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10213196
关键词：
Activated Lymphocyte Address Adolescent Advanced Malignant Neoplasm Agonist Animal Model Antineoplastic Protocols Antitumor Response Area Authorship Automobile Driving BARD1 gene BRCA1 gene Bioinformatics CD8-Positive T-Lymphocytes Cancer Biology Cell Surface Proteins Cell model Cells Cellular biology Childhood Cancer Treatment Chimeric Proteins Coculture Techniques Combination immunotherapy Combined Modality Therapy Committee Members Complement Computer Analysis Cyclic GMP DNA DNA Damage DNA Repair Data Defect Development Plans Diagnosis Doxorubicin EWS-FLI1 fusion protein Educational Status Educational workshop Environment Ewings sarcoma Feedback Fostering Gene Activation Germ-Line Mutation Goals Grant Growth Human IRF1 gene Immune Immune checkpoint inhibitor Immune response Immunobiology Immunology Immunotherapeutic agent Immunotherapy Impairment In Vitro Individual Infiltration Inflammatory Interferon Activation Investigation K-Series Research Career Programs Knowledge Laboratories Literature Location Malignant Bone Neoplasm Malignant Childhood Neoplasm Malignant Neoplasms Manuscripts Mediating Mentors Mutation Oncogenic Pathway interactions Patients Pediatric Oncologist Pediatric Oncology Physicians Poly(ADP-ribose) Polymerases Radiation Regulation Relapse Research Sampling Science Scientist Seasons Signal Transduction Specimen Stimulator of Interferon Genes T cell response T-Lymphocyte Technical Expertise Techniques Testing Training Training Technics Tumor Cell Biology Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Universities Up-Regulation Vocational Guidance Woman Work anti-tumor immune response anticancer research base cancer cell career career development checkpoint inhibition checkpoint therapy cytokine cytotoxic CD8 T cells efficacy evaluation gene repair homologous recombination humanized mouse immune checkpoint immunogenicity immunoregulation improved in vivo inhibitor/antagonist malignant breast neoplasm meetings mouse model neoplastic cell patient subsets pre-clinical programmed cell death ligand 1 programs recruit repair function response skills tumor tumor DNA tumor immunology tumor-immune system interactions

项目摘要

The goal of this career development award is for the applicant to expand her knowledge and technical expertise in tumor immunology and bioinformatic analyses in order to apply these new skills to investigation of the childhood cancer Ewing sarcoma. Relapsed Ewing sarcoma is nearly uniformly fatal, and thus new treatment approaches are desperately needed. A growing number of immune-based therapies are now being incorporated into pediatric cancer treatment protocols. Thus, in order to be a successful clinician scientist directing a cutting- edge research program in Ewing sarcoma, it is essential that the applicant gain expertise in tumor immunobiology. Currently, very little is understood about regulation of the Ewing sarcoma tumor immune microenvironment. This proposal addresses the interplay of two broadly important facets of pediatric cancer research: DNA damage repair and tumor immune response. This proposed work specifically examines the ability of DNA damage to activate Ewing tumor cell immunoregulatory pathways. The proposed aims will utilize a combination of in vitro cell co-culture analyses, in vivo tumor animal modeling and human specimen analyses in order to address this important topic. The applicant has chosen a primary mentor who is an expert in immune/inflammatory signaling in cancer, and a co-mentor with expertise in T-cell biology and advanced immunology techniques. Additionally, the applicant has constructed a physician-scientist career mentoring committee and network of collaboartors including individuals with expertise in Ewing sarcoma, humanized mouse models, DNA damage repair, the tumor immune-microenvironment, and bioinformatic analyses. As a team, the mentor, co-mentor, committee members and collaborators are dedicated to providing the applicant with technique training in tumor immunology and advanced cancer biology, as well as critical feedback on grants and manuscripts and career guidance. The primary mentor and co-mentor are invested in guiding the applicant toward a highly successful career as physician scientist by transitioning her to senior authorship on manuscripts, preparing her to start an independent laboratory and encouraging her to directly mentor scientists and clinicians at various levels of training. The University of Pittsburgh is an outstanding environment in which to develop a career and expand a research program in tumor immunobiology. The applicant’s career development plan takes full advantage of the many unique offerings at Pittsburgh including face-to-face career development workshops with seasoned scientists, participation in the Pittsburgh Women in Science forum, graduate level tumor immunobiology and bioinformatics courses and opportunities for presentation of work-in-progress at the University of Pittsburgh Cancer Immunology Program meetings. With the enthusiastic support and exceptional scientific expertise of her mentor and co-mentor, the applicant is eager to gain specific training in tumor immunobiology and bioinformatic analyses and to launch an independent research career as a pediatric oncologist physician scientist studying Ewing sarcoma at the University of Pittsburgh.

该职业发展奖的目标是申请人扩大她的知识和技术专长在肿瘤免疫学和生物信息学分析中，将这些新技能应用于研究儿童癌症肉瘤。复发的尤因肉瘤几乎是统一致命的，因此是新的治疗方法迫切需要方法。现在正在纳入越来越多的基于免疫的疗法进入小儿癌症治疗方案。为了成为成功的临床科学家，尤因肉瘤的边缘研究计划，申请人必须获得肿瘤的专业知识至关重要免疫生物学。目前，关于EWING肉瘤肿瘤免疫的调节几乎没有理解微环境。该提议涉及两个大致癌症方面的相互作用研究：DNA损伤修复和肿瘤免疫反应。这项建议的工作专门研究了能力 DNA损伤激活尤林肿瘤细胞免疫调节途径。拟议的目标将利用体外细胞共培养分析，体内肿瘤动物建模和人类标本分析的结合为了解决这个重要主题。申请人选择了主要的精神，他是专家癌症中的免疫/炎症信号传导，以及具有T细胞生物学专业知识和晚期专业知识的同事免疫学技术。此外，适用的人构建了身体科学家的职业心理委员会和合作者网络，包括具有尤因肉瘤专业知识的个人，人源化鼠标模型，DNA损伤修复，肿瘤免疫微环境和生物信息学分析。作为一个团队导师，同事，委员会成员和合作者致力于向申请人提供肿瘤免疫学和晚期癌症生物学的技术培训，以及对赠款和赠款的重要反馈手稿和职业指导。主要的导师和联合学者用于指导申请人通过将她过渡到手稿的高级作者身份，致力于成为物理科学家的职业生涯，准备她开始一个独立的实验室，并鼓励她直接精神科学家和临床医生在各种培训级别上。匹兹堡大学是一个杰出的环境职业并扩大肿瘤免疫生物学研究计划。申请人的职业发展计划匹兹堡的许多独特报价的充分优势，包括面对面的职业发展研讨会与经验丰富的科学家一起，参加匹兹堡妇女参加科学论坛，研究生级肿瘤免疫生物学和生物信息学课程以及在进行工作的机会匹兹堡大学癌症免疫学计划会议。在热情的支持和卓越的支持下申请人渴望获得肿瘤的特定培训免疫生物学和生物信息学分析，并从事独立研究职业肿瘤学家的物理科学家在匹兹堡大学研究尤因肉瘤。