Angiogenin in ALS Pathobiology and Therapy

描述（由申请人提供）：本提案的目的是阐明血管生成素在肌萎缩侧索硬化症（ALS）病理生物学中的作用，并检查血管生成素蛋白在ALS治疗中的治疗潜力。假设血管生成素在运动神经元功能中发挥作用，并且血管生成素蛋白的全身治疗将防止运动神经元变性，并改善ALS患者的运动肌肉功能并延长其生存期。这一假设是从已发表的工作中制定的，即在ALS患者中发生ANG的功能丧失突变，并且血管生成素在胎儿和成人脊髓的运动神经元中强烈表达。我们的初步研究表明，血管生成素的表达在人类ALS患者的脊髓和发展ALS样症状的SOD 1G 93 A小鼠的脊髓中减少。与WT血管生成素蛋白防止缺氧诱导的运动神经元死亡的报道一起，可以预期血管生成素对ALS患者的运动神经元变性的保护作用。此外，我们已经证明，施用的血管生成素蛋白到达脊髓并改善SOD 1G 93 A小鼠的运动肌肉功能，并使它们的存活延长4周。我们将1）创建条件性和诱导性Ang 1敲除小鼠，并表征血管生成素在发育和ALS病理学中的作用; 2）生成组织和时间特异性ANG：SOD 1G 93 A双转基因小鼠，并检查ANG过表达对SOD 1G 93 A诱导的运动神经元毒性的影响; 3）优化SOD 1G 93 A小鼠中血管生成素蛋白的治疗活性。我们期望本研究的结果将描述血管生成素在ALS发病机制中的作用，并阐明血管生成素的神经元保护活性的机制。我们还期望获得血管生成素治疗SOD 1G 93 A小鼠的最佳给药方案、耐受性、毒性和药代动力学，并使用这些数据指导进一步的临床前和临床研究。

DESCRIPTION (provided by applicant): The objective of this proposal is to elucidate the role of angiogenin in amyotrophic lateral sclerosis (ALS) pathobiology and to examine the therapeutic potential of angiogenin protein in ALS treatment. The hypothesis is that angiogenin plays a role in motor neuron function and that systemic treatment with angiogenin protein will prevent motor neuron degeneration and will improve the motor muscular function of ALS patients and prolong their survival. This hypothesis is formulated from published work that loss-of-function mutations of ANG occur in ALS patients and that angiogenin is strongly expressed in motor neurons of both fetal and adult human spinal cord. Our preliminary studies have shown that angiogenin expression is decreased in the spinal cord of human ALS patients and in that of SOD1G93A mice that develop ALS-like symptoms. Together with the report that WT angiogenin proteins prevent hypoxia-induced motor neuron death, a protective role of angiogenin against motor neuron degeneration in ALS patients can be expected. Moreover, we have shown that i.p.-administered angiogenin protein reaches the spinal cord and improves the motor muscular function of SOD1G93A mice and prolongs their survival by 4 weeks. We are going to 1) create conditional and inducible Ang1 knockout mice and characterize the role of angiogenin during development and in ALS pathology; 2) generate tissue- and time-specific ANG:SOD1G93A double transgenic mice and examine the effect of ANG overexpression on SOD1G93A-induced motor neuron toxicity; and 3) optimize the therapeutic activity of angiogenin protein in SOD1G93A mice. We expect that the outcome of this study will characterize the role of angiogenin in ALS pathogenesis and will elucidate the mechanism of neuron protective activity of angiogenin. We also expect to obtain an optimal dosing regimen, tolerability, toxicity, and pharmacokinetics of angiogenin in the treatment of SOD1G93A mice and to use these data to guide further preclinical and clinical studies.