The goal of this proposal is to determine the role of WD40 repeat containing protein 36 (WDR36) in the pathogenesis of adult-onset primary open-angle glaucoma (POAG). This will be accomplished using mainly the zebrafish model system. Glaucoma is a heterogeneous group of blinding diseases affecting 70 million people worldwide. The disease causes neurodegeneration of retinal ganglion cells and the optic nerve, resulting in visual field deficits. The first symptom experienced is vision loss, and by this time permanent nerve damage has already occurred. Adult-onset POAG is the most common form of glaucoma, and is very prevalent in the aging population. For example, 7% of Americans age 79 and over are affected by POAG, while 1.9% age 40 an over are affected. The genetics of POAG are complex, with multiple genes acting in concert to cause disease. Currently, only three genes have been determined to cause POAG. The most recently described is WDR36. The function of the gene and its role in disease pathogenesis are unknown, but sequence alignment and domain structure analysis have lead to the hypothesis that it is the homolog of the yeast nucleolar gene, utp21. Utp21 is required for biogenesis of mature ribosomes and is important for cell proliferation. Zebrafish with insertional mutations is both copies of wdr36 die during development, with small eyes, a small head, bilateral cataracts and a necrotic liver.
The first aim of this proposal will be to study the cellular functions of wdr36 in the zebrafish and in cell culture.
The second aim will be to characterize the role of wdr36 in development.
The third aim will be to mimic human adult-onset POAG by studying wdr36 heterozygous mutant fish during aging. Understanding the genes, such as WDR36, involved in the complex genetics of POAG will aid in the development of novel screening and treatment options for patients at risk or suffering from glaucoma. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30AG029763-01
Application #
7225319
Study Section
Special Emphasis Panel (ZRG1-F01-N (20))
Program Officer
Chen, Wen G
Project Start
2007-04-01
Project End
2013-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
1
Fiscal Year
2007
Total Cost
$30,172
Indirect Cost
Name
Medical College of Wisconsin
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226