Pre-mRNA splicing is a critical step in mammalian gene expression. Defects in pre-mRNA splicing cause a large number of human diseases. Recent studies have identified mutations in three genes encoding general splicing factors, HPRP3, PRPC8, or PRPF31, as genetic defects causing autosomal dominant forms of retinitis pigrnentosa (adRP). The molecular mechanisms underlying such genetic defects remain to be elucidated. In our preliminary study, we have established primary retinal neuron cultures and found that expression of mutant PRPF31 proteins reduce the survival of retinal neurons. We propose to apply our expertise in studying pre-mRNA splicing regulation, programmed cell death and neurodegeneration to investigating the pathogenetic mechanisms underlying RP-causing mutations in human PRPF31 gene. We plan to use cell culture systems to examine the activities of wild-type and RP-mutant forms of PRPF31. We will search for target genes for PRPF31 using microarray and biochemical approaches. We will examine functional mechanisms by which PRPF31 mutations lead to retinal degeneration. This study will reveal potential new players in the pathogenesis of retinal degeneration. It is highly likely that the proposed study will contribute to understanding the basic mechanism of pre-mRNA splicing regulation and provide insights into the pathogenesis of adRP. This study will not only help in our understanding of adRP but also likely provide new information on other neurodegenerative disorders. Furthermore, correcting the underlying splicing defects will make inroads toward new treatment for these diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY014576-01A1
Application #
6732236
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Program Officer
Dudley, Peter A
Project Start
2004-05-01
Project End
2009-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
1
Fiscal Year
2004
Total Cost
$377,500
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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