DNA Damage and Immunogenicity in Ewing Sarcoma

这个职业发展奖的目标是让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，以应用这些新技术的调查， 儿童癌症尤因肉瘤。复发性尤文肉瘤几乎是一致致命的，因此新的治疗方法 迫切需要采取各种办法。越来越多的基于免疫的疗法现在正在被纳入 儿科癌症治疗方案。因此，为了成为一个成功的临床科学家指导切割- 边缘研究计划在尤文肉瘤，这是至关重要的，申请人获得专业知识，在肿瘤 免疫生物学目前，对尤文肉瘤肿瘤免疫调节的了解很少， 微环境该提案涉及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。这项拟议的工作具体审查的能力 DNA损伤激活尤文肿瘤细胞免疫调节途径。拟议目标将利用一个 体外细胞共培养分析、体内肿瘤动物建模和人类样本分析的组合， 为了解决这个重要的问题。申请人选择了一位主要导师，他是 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 免疫学技术。此外，申请人还建立了一个医生-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 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人提供 肿瘤免疫学和先进癌症生物学的技术培训，以及对赠款和 手稿和职业指导。主要导师和共同导师投入指导申请人 通过将她转变为手稿的高级作者， 帮助她建立一个独立的实验室，并鼓励她直接指导科学家和临床医生 在不同层次的培训。匹兹堡大学是一个优秀的环境，在其中发展一个 职业生涯和扩大肿瘤免疫生物学的研究计划。申请人的职业发展计划 充分利用匹兹堡的许多独特的课程，包括面对面的职业发展研讨会 与经验丰富的科学家，参与匹兹堡妇女在科学论坛，研究生水平的肿瘤 免疫生物学和生物信息学课程和机会，介绍正在进行的工作， 匹兹堡大学癌症免疫学项目会议。在热情的支持和卓越的 由于她的导师和合作导师的科学专业知识，申请人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，并启动一个独立的研究生涯，作为一个儿科 他是匹兹堡大学研究尤因肉瘤的肿瘤学家。

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.