Angiogenin in ALS Pathobiology and Therapy

描述(申请人提供)：这项建议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，并研究血管生成素蛋白在ALS治疗中的治疗潜力。假说是血管生成素在运动神经元功能中起作用，全身应用血管生成素蛋白可以防止运动神经元变性，改善ALS患者的运动肌肉功能，延长其生存时间。这一假说是从已发表的工作中提出的，即ALS患者中存在Ang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都有强烈表达。我们的初步研究表明，血管生成素在人类ALS患者和出现ALS样症状的SOD1G93A小鼠的脊髓中的表达减少。与WT血管生成素蛋白防止缺氧诱导运动神经元死亡的报告一起，血管生成素对ALS患者运动神经元变性的保护作用是可以预期的。此外，我们还表明，腹腔注射血管生长素蛋白可以到达脊髓，改善SOD1G93A小鼠的运动肌肉功能，并延长它们的生存时间4周。我们将1)建立有条件的和可诱导的Ang1基因敲除小鼠，并研究血管生成素在发育和ALS病理中的作用；2)建立组织和时间特异性的Ang：SOD1G93A双转基因小鼠，并检测Ang过表达对SOD1G93A诱导的运动神经元毒性的影响；以及3)优化血管生成素蛋白在SOD1G93A小鼠中的治疗活性。我们期望这项研究的结果将表征血管生成素在ALS发病机制中的作用，并将阐明血管生成素的神经保护作用机制。我们还期望获得治疗SOD1G93A小鼠的血管生长素的最佳给药方案、耐受性、毒性和药代动力学，并利用这些数据指导进一步的临床前和临床研究。 公共卫生相关性：肌萎缩侧索硬化症是一种毁灭性的运动神经元退行性疾病，没有有效的治疗方法。这项建议的目的是了解血管生成素在运动神经元生理和功能中的作用，并评估血管生成素在ALS治疗中的治疗活性。

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. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis is a devastating motor neuron degenerative disease without effective treatment. The goal of this proposal is to understand the role of angiogenin in motor neuron physiology and function, and to assess therapeutic activity of angiogenin in ALS treatment.