DNA Damage and Immunogenicity in Ewing Sarcoma

尤文肉瘤中的 DNA 损伤和免疫原性

• 批准号: 10605340
• 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
• 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/10605340
• 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; Dedications; 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; Immunotherapy; Impairment; In Vitro; Individual; Infiltration; Inflammatory; Interferon Activation; Investigation; Investments; 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) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Radiation; Regulation; Relapse; Research; Sampling; Science; Scientist; Seasons; Signal Transduction; Specimen; Stimulator of Interferon Genes; T cell infiltration; T cell response; T-Lymphocyte; Technical Expertise; Techniques; Testing; Training; Training Technics; Tumor Cell Biology; Tumor-Infiltrating Lymphocytes; Universities; Up-Regulation; Vocational Guidance; Woman; Work; anti-tumor immune response; anticancer research; 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; malignant breast neoplasm; meetings; mouse model; neoplastic cell; novel therapeutic intervention; patient subsets; pre-clinical; programmed cell death ligand 1; programs; recruit; repair function; response; skills; tumor; tumor DNA; tumor immunology; tumor-immune system interactions

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.

这一职业发展奖的目标是让申请者扩大自己的知识和技术专长。 在肿瘤免疫学和生物信息学分析中，以便将这些新技术应用于 儿童癌症尤因肉瘤。复发的尤文肉瘤几乎都是致命的，因此新的治疗方法 迫切需要采取措施。越来越多的以免疫为基础的疗法正在被纳入 儿科癌症治疗方案。因此，为了成为一名成功的临床科学家，指导切割- 尤文肉瘤的边缘研究计划，申请人必须获得肿瘤方面的专业知识 免疫生物学。目前，人们对尤文肉瘤免疫的调控知之甚少。 微环境。这项建议解决了儿科癌症两个广泛重要方面的相互作用。 研究：DNA损伤修复和肿瘤免疫反应。这项拟议的工作专门考察了 DNA损伤激活尤文肿瘤细胞免疫调节通路。拟议的目标将利用 结合体外细胞共培养分析、体内肿瘤动物模型和人体标本分析 以解决这一重要话题。申请者已经选择了一位在以下方面的专家的主要导师 癌症中的免疫/炎症信号，以及具有T细胞生物学和先进技术专业知识的共同导师 免疫学技术。此外，申请者还构建了医生-科学家职业指导 委员会和共谋者网络，包括在尤因肉瘤、人源化小鼠方面有专长的个人 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、共同导师、委员会成员和合作者致力于为申请者提供 肿瘤免疫学和先进癌症生物学方面的技术培训，以及对赠款和 手稿和职业指导。主要导师和共同导师负责指导申请者 通过将她转变为手稿的资深作者，她成为了一名非常成功的内科科学家， 为她开办独立实验室做好准备，并鼓励她直接指导科学家和临床医生 在不同级别的培训中。匹兹堡大学是一个优秀的环境，在这个环境中 职业生涯，并扩大肿瘤免疫生物学的研究计划。申请人的职业发展计划需要 充分利用匹兹堡的许多独特课程，包括面对面的职业发展研讨会 与经验丰富的科学家一起，参加匹兹堡女性科学论坛，研究生级别的肿瘤 免疫生物学和生物信息学课程和介绍进展中工作的机会 匹兹堡大学癌症免疫学项目会议。在热情的支持和非凡的支持下 由于她的导师和共同导师的科学专长，申请者渴望获得肿瘤方面的专门培训。 免疫生物学和生物信息学分析，并作为儿科医生开始独立的研究生涯 匹兹堡大学肿瘤学家、内科医生、科学家，研究尤因肉瘤。