PKA modulation of hedgehog: mouse medulloblastoma model

Hedgehog 的 PKA 调节：小鼠髓母细胞瘤模型

• 批准号: 7360308
• 负责人: JAMES A WASCHEK
• 金额: $ 28.64万
• 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/7360308
• 关键词: Accounting; Adenylate Cyclase; Affinity; Animal Model; Area; Brain; Cell Line; Cells; Child; Childhood Brain Neoplasm; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytoplasmic Granules; Data; Development; Drosophila genus; Erinaceidae; Frequencies; Gene Expression; Genes; Growth; Human; Hyperactive behavior; Hyperplasia; Incidence; Ligands; Malignant neoplasm of brain; Messenger RNA; Mitotic; Modeling; Morbidity - disease rate; Mus; Mutation; Nervous system structure; Neural tube; Neurons; Neuropeptides; Pathogenesis; Pathway interactions; Patients; Peptide Receptor; Peptides; Physiological; Pituitary Gland; Rate; Resources; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; Survival Rate; System; Testing; Thinking; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor-Derived; Ventricular; Vertebrates; Week; hindbrain; improved; medulloblastoma; mouse model; mutant; neuroblast; receptor; smoothened signaling pathway; sonic hedgehog receptor; therapeutic target; tumor

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，占小儿脑肿瘤的20-25％。该肿瘤患者的存活率约为50％，但是消除脑发育过程中儿童肿瘤所需的治疗率会导致明显的额外发病率。在这些肿瘤中，声音刺猬（SHH）信号级联反应的过度活化似乎在高频中发生。因此，在该信号通路中过度活跃的髓母细胞瘤的动物模型是研究这些肿瘤的起始和传播的潜在宝贵资源，也可以用于测试潜在的疗法。该建议研究了一种新的小鼠模型，其中声音刺猬（SHH）信号在产生髓母细胞瘤的细胞中得到了增强。这些小鼠包含两个靶向突变，一个在编码SHH受体/肿瘤抑制剂1（PTC-1）的基因中，另一个在编码分泌神经肽PACAP（垂体腺苷酸酯循环酶激活肽）的基因中。 PACAP受体在生发区域被共定位，而大脑被认为会引起髓母细胞瘤。建议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双重杂合小鼠的髓母细胞瘤发病率为66％（比PTC-1小鼠为15％），平均发病率明显更快（16周，PTC-1的28周）。在此提案中，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，以更好地了解髓母细胞瘤中PACAP/PKA途径的重要性以及PKA与刺猬途径相互作用的机制。