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让申请人扩展其知识和技术专长肿瘤免疫学和生物信息分析，以便将这些新技能应用于研究儿童癌症尤文肉瘤复发性尤文肉瘤几乎都是致命的，因此需要新的治疗方法。现在迫切需要越来越多的基于免疫的疗法。因此，为了成为指导切割的成功临床科学家。尤文肉瘤的边缘研究项目，申请人获得肿瘤方面的专业知识至关重要目前，人们对尤文肉瘤肿瘤免疫的调节知之甚少。该提案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的能力。 DNA损伤以激活尤文肿瘤细胞免疫调节途径。结合体外细胞共培养分析、体内肿瘤动物模型和人体样本分析为了解决这个重要的话题，申请人选择了一位在该领域的专家的主要导师。癌症中的免疫/炎症信号传导，以及具有 T 细胞生物学和高级专业知识的共同导师此外，申请人还建立了医生科学家职业指导。委员会和合作者网络，包括具有尤文肉瘤、人源化小鼠专业知识的个人模型、DNA 损伤修复、肿瘤免疫微环境和生物信息学分析。导师、共同导师、委员会成员和合作者致力于为申请人提供肿瘤免疫学和先进癌症生物学的技术培训，以及对拨款和资助的关键反馈主要导师和共同导师致力于指导申请人。通过将她转变为手稿的高级权威，走向作为医学科学家的高度成功的职业生涯，准备她建立一个独立的实验室，并鼓励她直接指导科学家和反叛者匹兹堡大学为培养各种层次的人才提供了良好的环境。职业发展并扩大肿瘤免疫生物学的研究项目申请人的职业发展计划需要。充分利用匹兹堡的许多独特服务，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，研究生水平肿瘤免疫生物学和生物信息学课程以及在会议上展示正在进行的工作的机会匹兹堡大学癌症免疫学计划会议得到了热情的支持和特殊的支持。由于她的导师和共同导师的科学专业知识，申请人渴望获得肿瘤方面的具体培训免疫生物学和生物信息分析，并以儿科身份开展独立的研究生涯匹兹堡大学研究尤文肉瘤的肿瘤学家医师科学家。