Elucidating and exploiting the mechanisms by which IL-6 and IL-8 facilitate osteosarcoma metastasis

职业发展建议摘要 这个职业发展奖将支持博士的工作。Roberts，MD，PhD.这将为他提供 有独特的机会，发展他的调查技能，在一个保护和指导的环境。它将促进 产生足够的核心研究机构，使他能够成功地竞争R 01- 供资水平和向独立过渡。 瑞安是一个研究员在儿科血液学，肿瘤学，和骨髓移植在他的最后几个月， 训练他在俄亥俄州州立大学完成了综合生物医学科学博士学位， 肿瘤-宿主相互作用和肿瘤免疫学。他的研究成果证明了乳腺肿瘤细胞 与巨噬细胞相互作用，促进肿瘤的生长和扩散。他证明了 治疗性细胞因子方式可以使这些相同的巨噬细胞采取抗肿瘤行为。 他开始了他目前的工作，而在全国儿童医院儿科研究住院医师， 哥伦布，俄亥俄州，并继续在他的奖学金的工作。他的实验室已经证明IL-6和IL-8 在促进骨肉瘤细胞从循环系统募集到 肺和这些组织的生长。拟议的研究计划旨在通过以下方式描述这些机制： 这些细胞因子驱动转移过程，并探索靶向这些途径的潜力， 对于预防转移瘤的形成和治疗现有的肺转移瘤可能有： 目的1将确定肿瘤源性和肺源性IL-6和IL-8对转移的相对重要性。 目的2将确定介导该过程的细胞间信号通路，即， 与肿瘤细胞相互作用的细胞以及其他细胞因子。 目的3将测试IL-6和IL-8通路中断对于预防转移的治疗潜力。 并确定是否有一段时间的机会，周围的肿瘤切除， 可能特别相关。 与本研究提案相结合的是一个全面的职业发展计划，该计划建立在以下基础之上： 坚实的指导。瑞安将享受结构化和持续的指导，从： Stephen Lessnick，医学博士，博士，他的中心主任，国际知名的肉瘤生物学家， 独立地描述了尤文肉瘤中驱动恶性肿瘤的分子病理生理学。 Timothy Cripe，MD，PhD，他的部门主席，国际知名的溶瘤病毒专家， 他领导了自己的几项一期临床试验。 彼得霍顿，博士，他的前中心主任和主要导师期间，一个国际专家， 临床前药物评估和NCI儿科临床前测试计划的负责人。 丹尼斯·古特雷斯博士，肌肉生物学和横纹肌肉瘤方面非常成功的专家， 在炎症信号通路的解剖方面有着特殊的专业知识。 林嘉宇博士，他所在部门的同事，在炎症受体方面拥有丰富的经验 生物化学，包括目标验证。 Charles Keller，医学博士，儿科肉瘤小鼠模型的国际专家。 他的职业发展计划概述了结构化的指导，课程和研讨会的组合， 参与既定的常设研究计划，旨在帮助他实现以下目标：1） 提高他在细胞间和细胞内信号通路的机械解剖方面的技能，2）利用 基因工程小鼠模型，以解决机制问题，3）熟悉该过程 临床前药物开发，4）融入儿科肉瘤的科学界 5、成为一个有效率的作家。该计划包括负责任行为的培训 他的研究机构要求他通过正在进行的课程和研究伦理课程进行研究。 研究肿瘤-宿主相互作用介导的骨肉瘤转移提供了一个理想的模型系统 来研究实体瘤转移的生物学。本提案中使用的模型不仅 有助于阐明介导这一过程的生物学机制，但也是极好的 可以评估治疗干预的临床前评价的系统。非常需要 临床上可行的治疗策略，针对骨肉瘤和许多其他实体瘤的转移过程 肿瘤的将这项研究与明确和全面的职业发展计划相结合 再加上来自经验丰富和有能力的导师的支持，将使瑞安做好准备，这样他就可以茁壮成长， 他准备并开始向作为一名医生科学家的独立性进行结构性的过渡。

CAREER DEVELOPMENT PROPOSAL SUMMARY This Career Development award will support the work of Dr. Ryan D. Roberts, MD, PhD. It will provide him with unique opportunities to develop his investigative skills in a protected and mentored setting. It will facilitate the generation of a sufficient core body of research so that he will be able to compete successfully for R01- level funding and transition to independence. Ryan is a Fellow in Pediatric Hematology, Oncology, and Bone Marrow Transplant in his final months of training. He completed a PhD in Integrated Biomedical Sciences at the Ohio State University, where he studied tumor-host interactions and tumor immunology. His graduate work demonstrated how breast tumor cells interact with macrophages in ways that facilitate the growth and spread of those tumors. He demonstrated that therapeutic cytokine modalities could make those same macrophages adopt anti-tumor behaviors. He began his current line of work while a Pediatric Research Resident at Nationwide Children's Hospital in Columbus, Ohio and has continued that work during his fellowship. His lab has shown that IL-6 and IL-8 play important roles in the dynamics that facilitate recruitment of osteosarcoma cells from the circulation into the lung and growth with those tissues. The proposed research plan aims to characterize the mechanisms by which these cytokines drive the metastatic process and to explore the potential that targeting these pathways might have for preventing metastases from forming and for treating existing lung metastases:  Aim 1 will determine the relative importance of tumor-derived and lung-derived IL-6 and IL-8 to metastasis.  Aim 2 will identify the intercellular signaling loops that mediate the process, namely, which resident lung cells the tumor cells interact with and what other cytokines are involved.  Aim 3 will test the therapeutic potential of IL-6 and IL-8 pathway disruption for the prevention of metastasis and determine whether there is a period of opportunity surrounding tumor resection where such therapies might be particularly relevant. Integrated with this research proposal is a comprehensive career development plan, built on a backbone of solid mentorship. Ryan will enjoy structured and ongoing mentorship from:  Stephen Lessnick, MD, PhD, his Center Director, an internationally-renown sarcoma biologist who has independently described much of the molecular pathophysiology driving malignancy in Ewing sarcoma.  Timothy Cripe, MD, PhD, his Division Chair, an internationally respected expert in oncolytic viruses and pediatric sarcomas who heads several of his own phase I clinical trials.  Peter Houghton, PhD, his former center director and primary mentor during, an international expert in preclinical drug evaluation and head of the NCI's Pediatric Preclinical Testing Program.  Denis Guttridge, PhD, an extremely successful expert in muscle biology and rhabdomyosarcoma with particular expertise in the dissection of inflammatory signaling pathways.  Jiayuh Lin, PhD, a colleague within his Division who has extensive experience with inflammatory receptor biochemistry, including target validation.  Charles Keller, MD, an international expert in murine models of pediatric sarcomas. His career development plan outlines a combination of structured mentorship, coursework and workshops, and participation in established standing research programs designed to help him attain the following goals: 1) improve his skill in the mechanistic dissection of inter- and intra-cellular signaling pathways, 2) utilize genetically-engineered murine models to address mechanistic questions, 3) become familiar with the process of preclinical drug development, 4) become integrated into the scientific community of pediatric sarcoma research, and 5) become an efficient and effective writer. The plan includes training in the responsible conduct of research through ongoing coursework required by his institution and a course in research ethics. The study of tumor-host interactions that mediate metastasis in osteosarcoma provides an ideal model system in which to investigate the biology of solid tumor metastasis. The models used in this proposal not only facilitate elucidation of the biologic mechanisms which mediate this process, but also serve as excellent systems in which preclinical evaluation of therapeutic interventions can be assessed. There is great need for clinically viable treatment strategies that target the metastatic process in osteosarcoma and many other solid tumors. The integration of this research with a well-defined and comprehensive career development plan together with support from experienced and capable mentors will prepare Ryan well, so that he can thrive as he prepares for and begins a structured transition toward independence as a physician-scientist.