PKA modulation of hedgehog: mouse medulloblastoma model

描述（申请人提供）：髓母细胞瘤是儿童最常见的恶性脑肿瘤，占儿童脑肿瘤的20-25%。这种肿瘤患者的存活率约为50%，然而，在儿童大脑发育期间根除肿瘤所需的治疗导致显著的额外发病率。超音hedgehog （Shh）信号级联的过度活性似乎在这些肿瘤中高频发生。因此，在该信号通路中过度活跃的成神经管细胞瘤的动物模型是研究这些肿瘤的发生和传播的潜在宝贵资源，也可用于测试潜在的治疗方法。本研究研究了一种新的小鼠模型，其中Shh信号在产生成神经管细胞瘤的细胞中被增强。这些小鼠含有两个靶向突变，一个在编码Shh受体/肿瘤抑制因子patch -1 （ptc-1）的基因中，另一个在编码分泌神经肽PACAP（垂体腺苷酸环化酶激活肽）的基因中。PACAP受体共定位于大脑生发区，这被认为是产生成神经管细胞瘤的原因。PACAP通常通过蛋白激酶A （PKA）抑制Shh信号和Shh有丝分裂作用。初步数据表明，ptc-1/PACAP双杂合小鼠髓母细胞瘤发病率为66% (ptc-1小鼠为15%)，平均发病时间明显更快（ptc-1小鼠为16周，而ptc-1小鼠为28周）。在本提案中，我们将进一步表征该模型，并计划将其与衍生细胞系一起使用，以更好地了解PACAP/PKA通路在成神经管细胞瘤中的意义以及PKA与hedgehog通路相互作用的机制。

DESCRIPTION (provided by applicant): Medulloblastoma is the most common malignant brain tumor in children, accounting for 20-25% of pediatric brain tumors. The survival rate for patients with this tumor is about 50%, however the therapy required to eradicate the tumor in children during brain development results in significant additional morbidity. Overactivty of the sonic hedgehog (Shh) signaling cascade appears to occur at high frequency in these tumors. Thus, animal models with medulloblastoma tumors overactive in this signaling pathway are a potentially valuable resource to investigate the initiation and propagation of these tumors, and can also be used to test potential therapies. This proposal investigates a new mouse model in which sonic hedgehog (Shh) signaling is enhanced in the cells that give rise to medulloblastoma. These mice contain two targeted mutations, one in the gene encoding the Shh receptor/tumor suppressor patched-1 (ptc-1), and other in the gene encoding the secreted neuropeptide PACAP (pituitary adenylyl cyclase activating peptide). PACAP receptors are colocalized in the germinal areas the brain that are thought to give rise to medulloblastoma. It is proposed that PACAP normally inhibits Shh signaling and Shh mitogenic action via protein kinase A (PKA). Preliminary data indicate that ptc-1/PACAP double heterozygous mice have a medulloblastoma incidence of 66% (compared to 15% in ptc-1 mice) with an average onset that is significantly more rapid (16 weeks vs. 28 weeks in ptc-1). In this proposal, we will further characterize this model, and plan to use it along with the derived cell lines to better understand the significance of the PACAP/PKA pathway in medulloblastoma and the mechanism by which PKA interacts with the hedgehog pathway.