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（申请人提供）：髓母细胞瘤是儿童最常见的恶性脑肿瘤，占小儿脑肿瘤的20-25%。这种肿瘤患者的生存率约为 50%，但在大脑发育期间根除儿童肿瘤所需的治疗会导致显着的额外发病率。声音刺猬 (Shh) 信号级联的过度活跃似乎在这些肿瘤中频繁发生。因此，髓母细胞瘤在该信号通路中过度活跃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，并且也可用于测试潜在的疗法。该提案研究了一种新的小鼠模型，其中产生髓母细胞瘤的细胞中的声波刺猬（Shh）信号得到增强。这些小鼠含有两种靶向突变，一种是编码 Shh 受体/肿瘤抑制因子 patched-1 (ptc-1) 的基因，另一种是编码分泌型神经肽 PACAP（垂体腺苷酸环化酶激活肽）的基因。 PACAP 受体共定位于大脑的生发区，被认为会引起髓母细胞瘤。据推测，PACAP 通常通过蛋白激酶 A (PKA) 抑制 Shh 信号传导和 Shh 有丝分裂作用。初步数据表明，ptc-1/PACAP 双杂合小鼠的髓母细胞瘤发病率为 66%（相比之下，ptc-1 小鼠为 15%），平均发病速度明显更快（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，并计划将其与衍生的细胞系一起使用，以更好地理解 PACAP/PKA 通路在髓母细胞瘤中的重要性以及 PKA 与刺猬通路相互作用的机制。