Trk receptor mediated apoptosis of medulloblastoma cells

我们的总体目标是阐明Trk受体信号在小儿脑肿瘤成神经管细胞瘤中的作用。我们实验室和其他研究人员最近的工作表明，转染了TrkA受体的髓母细胞瘤细胞在受到NGF刺激时发生凋亡。这一观察结果具有重要的生物学意义，因为在所有其他被研究的细胞中，包括其他类型的肿瘤细胞，Trk受体激活促进分化（或增殖）和存活。我们假设内源性TrkA、TrkB和TrkC受体的激活会导致成神经管细胞瘤细胞死亡，而Trk受体的激活会抑制成神经管细胞瘤细胞在体内的生长、存活和扩散。我们的研究将通过使用从患者肿瘤样本中培养的原代髓母细胞瘤细胞，并在异种移植模型中分析Trk受体激活在体外和体内的影响，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的过度表达之间的冲突才能杀死成神经管细胞瘤细胞。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抑制（或进一步过表达）c-myc来确定其对细胞凋亡的影响来验证这一假设。由于Trk受体状态是与成神经管细胞瘤患者存活最明显相关的分子特征，因此了解Trk受体信号在成神经管细胞瘤中的作用具有重要的临床和治疗意义。通过结合来自患者样本的原发性髓母细胞瘤肿瘤细胞的研究，并在体外和体内研究中表达内源性Trk受体，本提案旨在确定Trk受体信号传导在髓母细胞瘤中的生物学作用。Paul Mischel博士是一名经委员会认证的神经病理学家，他曾在HHMI-UCSF的Louis F. Reichardt博士那里接受过一段时间的分子神经科学初步培训。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领先的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.莫布里和路易斯F.赖哈特作为共同导师。这个由国际公认的导师组成的团队致力于帮助米歇尔博士实现该提案的所有目标，并确保他发展成为一名杰出的独立研究者。

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.