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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065237-06
Application #
8608606
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gubitz, Amelie
Project Start
2010-03-15
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
$327,029
Indirect Cost
$121,350
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
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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
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