The candidate's long-term aims are to develop a better molecular understanding of photoreceptor cell death in retinal degenerative diseases, and to use this information to develop novel treatments for these conditions. Photoreceptor cell death is the final, irreversible step in the progression of blinding diseases such as retinitis pigmentosa and age-related macular degeneration. Limited treatment options are available for individuals with these conditions. One therapeutic strategy seeks to provide neurotrophic factors to the diseased retina in an effort to prolong photoreceptor cell survival. The GDNF family ligands (GFLs) in conjunction with their respective GDNF family receptors (GFRas) activate intracellular signaling through the Ret tyrosine kinase. These factors are potent survival factors for dopaminergic, sympathetic, and parasympathetic neurons. Members of the GDNF family have been localized to the retina, and may play important roles in retinal development and maintenance. The laboratory of the candidate's sponsor has been instrumental in defining the physiologic roles of many of the GDNF family members. The laboratory has all the available resources, including mouse models, antibodies, probes, and the expertise currently in place to facilitate successful completion of this research proposal. With the guidance of his sponsor, the candidate proposes to investigate the function of the GFLs in normal retinal development and to assess their ability to slow photoreceptor cell death in models of retinal degeneration. He will (1) determine the spatial and temporal expression patterns of GDNF family members in the normal murine retina, (2) determine the retinal phenotype produced by loss-of-function mutations in the GFLs, GFRas, and Ret, and (3) to investigate whether gain-of-function mutations in GFLs can slow photoreceptor cell death in mice with retinal degeneration.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08EY016140-01
Application #
6858852
Study Section
Special Emphasis Panel (ZEY1-VSN (06))
Program Officer
Dudley, Peter A
Project Start
2005-02-01
Project End
2010-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
1
Fiscal Year
2005
Total Cost
$156,224
Indirect Cost
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Brantley Jr, Milam A; Jain, Sanjay; Barr, Emily E et al. (2008) Neurturin-mediated ret activation is required for retinal function. J Neurosci 28:4123-35