Regulation- Medulloblastoma Growth by alpha-v integrins

描述（由申请人提供）： 托比·约翰·麦克唐纳，医学博士，接收 儿童医院儿科血液学/肿瘤学奖学金培训 洛杉矶从1994年至1998年，现在是儿科助理教授， 神经肿瘤学临床主任，儿童研究成员 儿童国家医疗中心（CNMC）研究所在华盛顿，DC。 他过去的培训和出版物都集中在丝氨酸的作用 蛋白酶和整合素在中枢神经系统肿瘤生长、侵袭和血管生成中的作用 神经系统肿瘤 使用体外和体内实验模型，他 最近 证明 的 α-V 整合素功能 到 促进 髓母细胞瘤生长。 进行这方面的研究，并保证 保护时间对一个独立的研究生涯的发展，博士。 麦克唐纳被授予艾弗里奖学金奖的儿童研究 1999年成立。 在这种支持下，麦克唐纳博士开发了一种反义核酸， 降低髓母细胞瘤α-v整合素表达水平的策略 这样这些分子在髓母细胞瘤中的精确功能就可以 进一步测试。 在指导临床科学家的支持下 麦克唐纳博士计划利用这一战略来确定 α-V整合素促进肿瘤细胞生长和存活的机制 髓母细胞瘤细胞 假设是α-v整合素 与整合素-配体复合物内的生长因子受体结合， 信号转导 该项目的具体目标是确定 成神经管细胞瘤α-V整合素减少对：1）生长因子和 受体表达，2）生长因子介导的增殖，存活和 2个中枢促生长信号转导通路的初始激活， 和3）实验性肿瘤生长和血管生成。 蛋白介导的信号 转导是麦克唐纳博士研究的新领域 通过共同指导 由整合素信号传导和生物学领域的领先专家玛丽安斯特普博士， 麦克唐纳预计将获得必要的技术技能和指导， 进行这项调查。 通过斯蒂芬·拉迪施博士的赞助， 儿童研究所的科学主任，以及 职业发展方案提供的正式培训， CNMC，本项目的短期科学目标是可以实现的。 在罗杰·帕克博士的额外指导下，一位著名的临床神经学家， 作为一名心理学家，麦克唐纳博士希望在美国发展独立的职业生涯。 3-5年内完成转化研究。 这项工作的长期目标是 为了拓宽我们对髓母细胞瘤生长的理解， 治疗可能会发展成为髓母细胞瘤的新疗法， 儿童常见的恶性脑肿瘤。

DESCRIPTION (provided by applicant): Tobey John MacDonald, M.D., received fellowship training in pediatric hematology/oncology at Children's Hospital Los Angeles from 1994-1998 and is now Assistant Professor of Pediatrics, Clinical Director of Neuro-Oncology, and Member of the Children's Research Institute of the Children's National Medical Center (CNMC) in Washington, DC. His past training and publications have centered on the role of serine proteases and integrins in the growth, invasion and angiogenesis of central nervous system tumors. Using in vitro and in vivo experimental models, he has recently demonstrated that alpha-v integrins function to promote medulloblastoma growth. To pursue this line of research, and to guarantee protected time toward the development of an independent research career, Dr. MacDonald was granted an Avery Scholarship Award by the Children's Research Institute in 1999. With this support, Dr. MacDonald developed an antisense strategy to reduce the level of alpha-v integrin expression by medulloblastoma cells so that the precise function of these molecules in medulloblastoma could be further tested. With the support of a Mentored Clinical Scientist Development Award, Dr. MacDonald plans to use this strategy to identify the mechanisms by which alpha-v integrins promote the growth and survival of medulloblastoma cells. The hypothesis is that alpha-v integrins cooperate with growth factor receptors within integrin-ligand complexes to potentiate signal transduction. The specific aims of the project are to determine the effect of medulloblastoma alpha-v integrin reduction on: 1) growth factor and receptor expression, 2) growth factor-mediated proliferation, survival and initial activation of 2 central growth-promoting signal transduction pathways, and 3) experimental tumor growth and angiogenesis. Integrin-mediated signal transduction is a new area of pursuit for Dr. MacDonald. With co-mentorship by Dr. Mary Ann Stepp, a leading expert in integrin signaling and biology, Dr. MacDonald is expected to obtain the technical skills and guidance necessary to carry out this investigation. Through the sponsorship of Dr. Stephan Ladisch, Scientific Director of the Children's Research Institute, and the resources and formal training provided by the Career Development Program established at CNMC, the short-range scientific goals of this project can be accomplished. With additional co-mentorship by Dr. Roger Packer, a renowned clinical neuro- o n cologist, Dr. MacDonald hopes to develop an independent career in translational research within 3-5 years. The long-range goal of this work is to broaden our understanding of medulloblastoma growth, so that novel biologic therapies may be developed into new treatments for medulloblastoma, the most common malignant brain tumor in children.