IGF-I Therapy for Hereditary Cerebeullar Ataxia

描述(申请人提供)：人类遗传性小脑性共济失调 由于小脑神经元的退化而逐渐发展起来 它们的传入和传出连接。这样做的长期目标是 研究是看看胰岛素样生长因子I(IGF-1)是否可以挽救 小脑突变小鼠小脑神经元的死亡，从而评估 胰岛素样生长因子-L治疗人类小脑性共济失调的潜力。互联网管理论坛--L 是一种最佳神经元增殖所需的合成生长因子， 分化和生存。胰岛素样生长因子-L的神经营养作用是最好的例证 在小脑发育过程中，胰岛素样生长因子-L及其受体基因 通常与出生后小脑的生长迅速相协调地表达。 当基因突变影响小脑生长时(WV和PCD小鼠)，胰岛素样生长因子-L的 在共济失调发生之前，生物活性通常会降低，这表明 正常的胰岛素样生长因子-L水平对小脑功能的完整性至关重要 细胞结构。另一方面，胰岛素样生长因子-L转基因小鼠的大脑更大 有更多的髓鞘和更多的脑细胞。在所有大脑区域中，小脑 受影响最大的。它的大小是正常大小的两倍，容量增加了92% 颗粒细胞和浦肯野细胞比野生型多20% 一窝产仔。充分评价胰岛素样生长因子-L治疗慢性阻塞性肺疾病的潜力 小脑性共济失调的治疗，本研究将：1.表征 胰岛素样生长因子-L保护小脑神经元的细胞机制2.交叉 用WV和PCD突变小鼠培育胰岛素样生长因子-L转基因小鼠 转IGF-I基因后的组织学、分子生物学和行为改变 包含零个、一个或两个WV或PCD等位基因的小鼠；以及3.评估 微囊化哺乳动物细胞携带胰岛素样生长因子-L的治疗作用 经设计可在刺激下合成并释放胰岛素样生长因子-L。结果是 这项调查将提供有关治疗方法的关键信息 胰岛素样生长因子-I治疗遗传性小脑性共济失调的潜力。

DESCRIPTION (Provided by applicant): In humans, hereditary cerebellar ataxias develop gradually resulting from the degeneration of cerebellar neurons and their afferent and efferent connections. The long term goal of this investigation is to see whether insulin-like growth factor I (IGF-1) can rescue cerebellar neurons from dying in cerebeltar mutant mice, thereby evaluating the therapeutic potential of IGF-l in treating cerebellar ataxia in humans. IGF-l is an anabolic growth factor required for optimal neuronal proliferation, differentiation and survival. IGF-l's neurotropic effect is best illustrated during the development of the cerebellum, where IGF-l and its receptor genes are normally expressed coordinately with the postnatal cerebellar growth spurt. When cerebellar growth is affected by gene mutations (wv and pcd mice), IGF-l's biological activity usually decreases before ataxia occurs, suggesting that normal IGF-l levels are pivotal for the functional integrity of cerebellar cytoarchitecture. On the other hand, IGF-l transgenic mice have bigger brains with more myelin and more brain cells. Among all brain regions, the cerebellum is affected most. It is twice the normal size, containing 92 percent more granule cells and 20 percent more Purkinje cells than are found in wild type littermates. To fully evaluate the therapeutic potential of IGF-l in the treatment of cerebellar ataxia, this investigation will: 1. characterize the cellular mechanism of IGF-l's neuroprotection for cerebellar neurons; 2. cross breed IGF-l transgenic mice with wv and pcd mutant mice and examine the resulting histology, molecular biology and behavior changes in IGF-I transgenic mice that contain zero, one or two wv or pcd alleles; and 3. evaluate the therapeutic effects of IGF-l delivered by microencapsulated mammalian cells engineered to synthesize and release IGF-l upon stimulation. The results of this investigation will provide crucial information about the therapeutic potential of IGF-I in treating hereditary cerebellar ataxia.