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 由于小脑神经元的退化而逐渐发展， 它们的传入和传出连接。长期目标是 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死亡，从而评估 IGF-I在治疗人类小脑共济失调中的治疗潜力。胰岛素样生长因子-1 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-I的亲神经作用最好地说明了 在小脑的发育过程中，IGF-1及其受体基因 通常与出生后小脑生长突增期协调表达。 当小脑的生长受到基因突变的影响时（wv和pcd小鼠），IGF-1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-1水平对于小脑的功能完整性是关键的。 细胞结构另一方面，IGF-I转基因小鼠的大脑更大， 有更多的髓磷脂和脑细胞在所有的大脑区域中，小脑 受影响最大。它是正常大小的两倍，含有92%以上 颗粒细胞和20%以上的浦肯野细胞比野生型 同窝出生的为了充分评估IGF-1在治疗糖尿病中的治疗潜力， 治疗小脑性共济失调，本研究将：1。表征 IGF-1对小脑神经元保护作用的细胞机制; 2.横 用wv和pcd突变小鼠培育IGF-1转基因小鼠， IGF-I转基因小鼠的组织学、分子生物学和行为学改变 含有零个、一个或两个wv或pcd等位基因的小鼠;和3.评价 微囊化哺乳动物细胞递送的IGF-1的治疗作用 被工程化以在刺激时合成和释放IGF-1。的结果 这项研究将提供有关治疗的关键信息， IGF-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.