Trk receptor mediated apoptosis of medulloblastoma cells

我们的总体目标是阐明Trk受体信号在儿童脑肿瘤髓母细胞瘤中的作用。我们实验室和其他研究人员最近的工作表明，当用NGF刺激时，TrkA受体转染的髓母细胞瘤细胞发生凋亡。这一观察结果是显著的和生物学上重要的，因为在所研究的所有其他细胞中，包括其他类型的肿瘤细胞，Trk受体活化促进分化（或增殖）和存活。我们假设内源性TrkA、TrkB和TrkC受体的激活导致髓母细胞瘤细胞死亡，并且Trk受体的激活抑制髓母细胞瘤细胞在体内的生长、活力和扩散。我们的研究将通过使用从患者肿瘤样品培养的原代髓母细胞瘤细胞，并通过分析Trk受体激活在异种移植模型中的体外和体内的作用来解决这些假设。我们假设Trk受体介导的凋亡需要Trk受体激活的信号通路和c-myc过度表达之间的冲突，以杀死髓母细胞瘤细胞。我们将通过检查细胞凋亡所需的Trk受体介导的信号通路和通过抑制（或进一步过度表达）c-myc来确定其对细胞凋亡的影响来测试这一假设。由于Trk受体状态是与髓母细胞瘤患者的生存率最明显相关的分子特征，因此了解Trk受体信号传导在髓母细胞瘤中的作用具有重要的临床和治疗意义。通过纳入对源自患者样本并表达内源性Trk受体的原发性髓母细胞瘤肿瘤细胞的体外和体内研究，该提案旨在确定Trk受体信号传导在髓母细胞瘤中的生物学作用。Paul Mischel博士是一名委员会认证的神经病理学家，并与Louis F.加州大学旧金山分校的Reichardt他提出了一个结构化的职业发展/培训计划，使他能够发展成为一名主要独立调查员所需的技能。他选择了哈维·赫希曼博士作为主要导师，威廉·C. Mobley和Louis F. Reichardt作为共同导师。这个国际公认的导师团队致力于帮助Mischel博士实现本提案的所有目标，并确保他发展成为一名出色的独立调查员。

Our overall goal in this proposal is to elucidate the role of Trk receptor signaling in the pediatric brain tumor medulloblastoma. Recent work by our laboratory, and by other investigators, demonstrates that medulloblastoma cells transfected with TrkA receptors undergo apoptosis when stimulated with NGF. This observation is remarkable and biologically important, because in all other cells studied, including other types of tumor cells, Trk receptor activation promotes differentiation (or proliferation) and survival. We hypothesize that activation of endogenous TrkA, TrkB and TrkC receptors causes medulloblastoma cells to die, and that activation of Trk receptors inhibits the growth, viability and spread of medulloblastoma cells in vivo. Our studies will address these hypotheses by using primary medulloblastoma cells cultured from patient tumor samples, and by analyzing the effects of Trk receptor activation both in vitro and in vivo in a xenograft model. We hypothesize that Trk receptor-mediated apoptosis requires a conflict between Trk receptor-activated signaling pathways and over-expression of c-myc in order to kill medulloblastoma cells. We will test this hypothesis by examining the Trk receptor-mediated signaling pathways that are required for apoptosis and by inhibiting (or further over-expressing) c-myc to determine its effect on apoptosis. Because Trk receptor status is the molecular feature that is most clearly associated with survival in medulloblastoma patients, understanding the role of Trk receptor signaling in medulloblastoma has important clinical and therapeutic implications. By incorporating studies on primary medulloblastoma tumor cells that are derived from patient samples, and that express endogenous Trk receptors, for both in vitro and in vivo studies, this proposal is designed to determine the biological role for Trk receptor signaling in medulloblastoma. Dr. Paul Mischel is a board certified neuropathologist, and has done a period of initial molecular neuroscience training with Dr. Louis F. Reichardt at HHMI-UCSF. He proposes a structured career development/training plan that will enable him to develop the skills necessary to become a leading independent investigator. He has chosen Dr. Harvey Herschman as the primary mentor, and Drs. William C. Mobley and Louis F. Reichardt as co- mentors. This team of internationally recognized mentors is committed to helping Dr. Mischel meet all of the aims of this proposal, and to ensure that he develops into an outstanding independent investigator.