Regulation- Medulloblastoma Growth by alpha-v integrins

描述(申请人提供)：托比·约翰·麦克唐纳，医学博士，已收到 儿童医院的儿童血液学/肿瘤学团契培训 1994年至1998年在洛杉矶，现在是儿科学助理教授， 神经肿瘤学临床主任，儿童研究会成员 位于华盛顿特区的国家儿童医学中心(CNMC)研究所。 他过去的训练和出版物都集中在丝氨酸的作用上 蛋白水解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，他已经 最近证明了α-v整合素的功能促进 髓母细胞瘤生长。从事这方面的研究，并保证 在独立研究事业的发展过程中受到保护的时间。 麦克唐纳被儿童研究中心授予艾弗里奖学金 该研究所于1999年成立。在这种支持下，麦克唐纳博士发展出了一种反义 髓母细胞瘤降低α-v整合素表达水平的策略 因此这些分子在髓母细胞瘤中的确切功能可以 需要进一步测试。在指导临床科学家的支持下 发展奖，麦克唐纳博士计划使用这一战略来确定 α-v整合素促进卵巢癌细胞生长和存活的机制 髓母细胞瘤细胞。假设是α-v整合素相互作用。 通过整合素-配体复合体中的生长因子受体增强 信号转导。该项目的具体目标是确定 髓母细胞瘤α-v整合素降低对：1)生长因子和 受体表达，2)生长因子介导的增殖、存活和 2条中枢促生长信号转导通路的初始激活， 3)实验性肿瘤生长和血管生成。整合素介导的信号 转导是麦克唐纳博士追求的一个新领域。共同指导 整合素信号和生物学方面的领先专家玛丽·安·斯特普博士。 预计麦克唐纳将获得必要的技术技能和指导 进行这项调查。通过斯蒂芬·拉迪什博士的赞助， 儿童研究所的科学主任，和资源 和由职业发展计划提供的正式培训 该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，著名的临床神经学家- 作为一名生物学家，麦克唐纳博士希望在 在3-5年内进行翻译研究。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，使新的生物学 髓母细胞瘤的治疗方法可能会发展成新的治疗方法，最 儿童常见的恶性脑瘤。

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.