This proposal focuses on the role of receptor tyrosine kinases in rendering motor neurons susceptible to neurodegenerative insults. TrkB is activated by its ligand, brain-derived neurotrophic factor. Several independent laboratories show that blocking TrkB activation in vitro can protect neurons from specific insults. Despite the heresy of these observations, we have seen the same phenomenon in vitro and in a specific in vivo circumstance.
In specific aim #1 we will investigate the temporal aspect of this process by putting the mutant SOD mouse on a TrkBF616A background. TrkBF616A can be specifically antagonized by the orally active, blood brain barrier permeable agent, 1NMPP1. A second receptor tyrosine kinase of interest is the Insulin/Insulin-like growth factor receptor (IGF-R). In model organisms (and recently in mice) a conserved stress resistance pathway is evoked when the activity of the IGF-R is reduced. The FOXO3a transcription factor plays a key role in this process in worms and flies, but its function in vertebrates is unknown.
In specific aim #2, we will determine if loss of FOXO3a ameliorates or exacerbates the mutant SOD mouse motor neuron disease. In the course of our investigations of FOXO3a, we found a marine sponge compound (Psammaplysene A, PA) that promotes nuclear localization of the transcription factor and is broadly neuroprotective in in vitro and in vivo models of neurodegeneration. While the evidence is strong that the compound works through FOXO3a, the precise molecular target is not known.
In specific aim #3, several approaches will be employed to find the target and pathway through which PA acts. Overall this work attempts to find new disease modifiers that slow the progression of motor neuron disease. If successful, new therapeutic targets will emerge.

Public Health Relevance

It is not known why specific neuronal populations are vulnerable to the toxic effects of neurodegenerative stimuli. In this proposal we will examine the role played by two signaling pathways in rendering motor neurons susceptible to insults relevant to Lou Gehrig's disease. In addition, we have identified a small molecule with remarkable neuroprotective activity. In this proposal we will determine the molecular target of this molecule and the signaling pathway through which it operates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052325-10
Application #
8787803
Study Section
Special Emphasis Panel (ZRG1-MDCN-A (03))
Program Officer
Gubitz, Amelie
Project Start
2006-02-15
Project End
2016-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
10
Fiscal Year
2015
Total Cost
$366,406
Indirect Cost
$147,656
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Boccitto, Marco; Lee, Nayoung; Sakamoto, Satoshi et al. (2017) The Neuroprotective Marine Compound Psammaplysene A Binds the RNA-Binding Protein HNRNPK. Mar Drugs 15:
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