Axon pruning or degeneration occurs widely during development, as part of axonal rearrangements following injury and in adult plasticity, and is a major pathological feature of most neurodegenerative diseases. However, the molecular mechanisms that initiate and execute axon degeneration in these diverse settings remain incompletely understood. Recently, we identified a caspase-dependent pathway that regulates axon degeneration both in vitro and in vivo. These findings have provided a new entry point for determining the molecular components that regulate axon degeneration. This proposal is focused on identifying key components of the biochemical pathway of caspase-dependent axon degeneration that lead to degeneration in the developing and diseased peripheral nervous system. We will use complementary approaches to (i) rapidly screen mice mutant for various pathway components to determine which ones regulate degeneration of developing sensory and motor axons in response to trophic deprivation in vitro, (ii) identify additional components of the degeneration pathway through biochemical analysis and siRNA screening, (iii) elucidate mechanisms of caspase regulation (iv) determine the contribution of the apoptotic pathway to developmental axon pruning in vivo, and (v) test for disease relevance by crossing relevant mutants to a mouse model of sensory axon degeneration. These studies will identify novel mechanisms regulating developmental and pathological axon degeneration, including potential therapeutic targets.

Public Health Relevance

Neurodegenerative diseases are a major cause of human suffering and pose a huge economic burden to our society. This project will provide new insights into the development of the nervous system as well as how these mechanisms by contribute to axon degeneration in neurodegenerative disease, which could provide new therapeutic strategies for treating these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS089786-01
Application #
8802250
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Mamounas, Laura
Project Start
2014-08-15
Project End
2019-05-31
Budget Start
2014-08-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$648,291
Indirect Cost
$265,819
Name
Rockefeller University
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065