IGF-I Therapy for Hereditary Cerebeullar Ataxia

描述（由申请人提供）：在人类中，遗传性小脑共济失调 由于小脑神经元退化而逐渐发育 他们的传入和传出连接。本次活动的长远目标 研究目的是看看胰岛素样生长因子 I (IGF-1) 是否可以挽救 小脑突变小鼠的小脑神经元死亡，从而评估 IGF-1 在治疗人类小脑性共济失调中的治疗潜力。胰岛素样生长因子-l 是最佳神经元增殖所需的合成代谢生长因子， 分化和生存。 IGF-l 的神经营养作用得到了最好的说明 在小脑发育过程中，IGF-l 及其受体基因 通常与出生后小脑生长突增相协调地表达。 当小脑生长受到基因突变影响时（wv 和 pcd 小鼠），IGF-l 的 生物活性通常在共济失调发生之前降低，这表明 正常的 IGF-l 水平对于小脑的功能完整性至关重要 细胞结构。另一方面，IGF-l 转基因小鼠的大脑更大 有更多的髓磷脂和更多的脑细胞。在所有脑区中，小脑 受影响最大。它是正常尺寸的两倍，含量多出 92% 颗粒细胞和浦肯野细胞比野生型多 20% 同窝的。全面评估 IGF-l 在以下疾病中的治疗潜力： 治疗小脑性共济失调，这项研究将： 1. 描述 IGF-1对小脑神经元保护作用的细胞机制； 2. 交叉 用wv和pcd突变小鼠培育IGF-l转基因小鼠并检查 IGF-I 转基因引起的组织学、分子生物学和行为变化 含有零个、一个或两个wv或pcd等位基因的小鼠； 3. 评估 微囊哺乳动物细胞递送的 IGF-1 的治疗作用 被设计为在刺激下合成和释放 IGF-1。结果 这项调查将提供有关治疗的重要信息 IGF-I 治疗遗传性小脑共济失调的潜力。

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.