Vesicular trafficking is crucial to cell function and survival, and deregulation of vesicular trafficking is associated with many human diseases, including neurodegenerative disease and peripheral neuropathy. The long-term goal of this research is to understand, at the molecular level, how vesicular trafficking is controlled in norma physiology and how this process becomes dysregulated in disease states. Charcot- Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy that has been known for more than 125 years, yet the pathogenic mechanisms underlying this disease remain unclear and there are currently no effective treatment for peripheral neuropathy. Human genetic studies reveal that missense mutations in SIMPLE, a ubiquitously expressed protein of unknown function, cause an autosomal dominant form of peripheral neuropathy known as CMT type 1C. The connection of SIMPLE to CMT underscores the importance of understanding the function of this understudied protein and opens up new avenues for investigating the molecular mechanisms that trigger peripheral neuropathy. Recently, the applicant's team found that SIMPLE is an early endosomal membrane protein involved in regulation of endosome-to- lysosome trafficking and generated the first CMT1C mouse model expressing a disease-linked human SIMPLE mutant protein. In this project, the applicant's team will build on their recent studies and use a combination of biochemical, molecular biological, cell biological, proteomic, and mouse genetic approaches to define the mechanisms of SIMPLE action in regulating vesicular trafficking and elucidate the pathogenic pathways by which SIMPLE mutations cause peripheral neuropathy. Successful completion of this project will advance our knowledge of the fundamental mechanisms governing vesicular trafficking and provide useful information needed for development of effective therapies to treat peripheral neuropathy and other human diseases with disturbed vesicular trafficking.

Public Health Relevance

Peripheral neuropathies such as Charcot-Marie-Tooth disease (CMT) are a group of debilitating disorders that affect the peripheral nervous system. This project will study the biological function of a novel protein named SIMPLE and define the molecular pathogenic mechanisms by which SIMPLE mutations cause peripheral neuropathy. The knowledge gained from the proposed research will promote the development of new therapeutic strategies for treating CMT and other peripheral nervous system disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092343-04
Application #
9542395
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Nuckolls, Glen H
Project Start
2015-09-30
Project End
2020-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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