PKA modulation of hedgehog: a mouse medulloblasto. model

Hedgehog 的 PKA 调节：小鼠髓母细胞。

• 批准号: 7046898
• 负责人: JAMES A WASCHEK
• 金额: $ 29.49万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046898
• 关键词: adenylate cyclase; biological signal transduction; cell line; cerebellum; cyclic AMP; disease /disorder model; embryo /fetus tissue /cell culture; enzyme mechanism; gene mutation; genetically modified animals; granule cell; kinase inhibitor; laboratory mouse; medulloblastoma; microarray technology; model design /development; molecular oncology; neoplasm /cancer genetics; neuropeptide receptor; neuropeptides; protein kinase A; protein protein interaction; small interfering RNA; terminal nick end labeling; transcription factor; tumor suppressor genes

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.

描述（由申请人提供）：髓母细胞瘤是儿童中最常见的恶性脑肿瘤，占儿童脑肿瘤的20-25%。患有这种肿瘤的患者的存活率约为50%，然而，在大脑发育期间根除儿童肿瘤所需的治疗导致显著的额外发病率。在这些肿瘤中，音刺猬（Shh）信号级联反应的过度活跃似乎以高频率发生。因此，具有在该信号传导通路中过度活跃的髓母细胞瘤肿瘤的动物模型是研究这些肿瘤的起始和传播的潜在有价值的资源，并且还可以用于测试潜在的疗法。该提案研究了一种新的小鼠模型，其中音刺猬（Shh）信号在引起髓母细胞瘤的细胞中增强。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patched-1（ptc-1）的基因中，另一个在编码分泌的神经肽PACAP（垂体腺苷酸环化酶激活肽）的基因中。PACAP受体共定位于被认为是引起髓母细胞瘤的大脑的生发区。PACAP通常通过蛋白激酶A（PKA）抑制Shh信号和Shh促有丝分裂作用。初步数据表明，ptc-1/PACAP双杂合子小鼠的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vs 28周）。在本提案中，我们将进一步表征该模型，并计划将其与衍生的细胞系沿着使用，以更好地了解PACAP/PKA通路在髓母细胞瘤中的意义以及PKA与hedgehog通路相互作用的机制。