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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gubitz, Amelie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Tufts University
United States
Zip Code
Sheng, Jinghao; Luo, Chi; Jiang, Yuxiang et al. (2014) Transcription of angiogenin and ribonuclease 4 is regulated by RNA polymerase III elements and a CCCTC binding factor (CTCF)-dependent intragenic chromatin loop. J Biol Chem 289:12520-34
Sheng, Jinghao; Yu, Wenhao; Gao, Xiangwei et al. (2014) Angiogenin stimulates ribosomal RNA transcription by epigenetic activation of the ribosomal DNA promoter. J Cell Physiol 229:521-9
Del Giudice, R; Monti, D M; Sarcinelli, C et al. (2014) Amyloidogenic variant of apolipoprotein A-I elicits cellular stress by attenuating the protective activity of angiogenin. Cell Death Dis 5:e1097
Li, Shuping; Sheng, Jinghao; Hu, Jamie K et al. (2013) Ribonuclease 4 protects neuron degeneration by promoting angiogenesis, neurogenesis, and neuronal survival under stress. Angiogenesis 16:387-404
Pizzo, Elio; Sarcinelli, Carmen; Sheng, Jinghao et al. (2013) Ribonuclease/angiogenin inhibitor 1 regulates stress-induced subcellular localization of angiogenin to control growth and survival. J Cell Sci 126:4308-19
Li, Shuping; Hu, Guo-Fu (2012) Emerging role of angiogenin in stress response and cell survival under adverse conditions. J Cell Physiol 227:2822-6
Li, Shuping; Yu, Wenhao; Hu, Guo-Fu (2012) Angiogenin inhibits nuclear translocation of apoptosis inducing factor in a Bcl-2-dependent manner. J Cell Physiol 227:1639-44
Li, Shuping; Yu, Wenhao; Kishikawa, Hiroko et al. (2010) Angiogenin prevents serum withdrawal-induced apoptosis of P19 embryonal carcinoma cells. FEBS J 277:3575-87
Li, Shuping; Hu, Guo-Fu (2010) Angiogenin-mediated rRNA transcription in cancer and neurodegeneration. Int J Biochem Mol Biol 1:26-35