The prime objective of this proposal is to produce a large animal model of macular degeneration using the gene ELOVL4. Transgenic pigs may be useful for the elucidation of the molecular mechanisms responsible for macular degeneration and for the development of therapeutic interventions. The pig's similarity to humans in size and retinal anatomy and physiology make it a logical choice for these experiments. Further, the production of transgenic pigs is a virtual surety. Only transgenic primates would provide a more accurate model, however, both the low supply of primates and low efficiency of these procedures will likely prevent gone transfer being a routine procedure in primates. Using a positional cloning approach, one of us (Zhang) has identified a disease gene called ELOVL4, which is responsible for an autosomal dominant form of Stargardt's-like macular dystrophy (STGD3) and autosomal dominant macular dystrophy (adMD). STGD3 and adMD are two related forms of inherited macular degeneration characterized by decreased visual acuity, macular atrophy, and fundus flecks. A single five base-pair deletion in the coding region of ELOVL4 is found in all affected members of four independent STGD3 families and one adMD family. The deletion generates a frame-shift mutation and results in loss of 51 amino acids at the C-terminus including a putative di-lysine ER targeting signal. ELOVL4 demonstrated cone and rod photoreceptor specific expression in the eye and encoded a putative transmembrane protein with similarities to the ELO family of proteins involved in elongation of very long chain fatty acids. Stargardt's macular dystrophy is the most common juvenile macular degeneration and shares many important clinical and histopathological similarities with AMD including an abnormal accumulation of lipofuscin in the RPE, atrophy of the RPE and overlying photoreceptor cells, and loss of central vision. ELOVL4 is the first gene involved in the biosynthesis of long chain fatty acids implicated in any form of photoreceptor degeneration. Studies of pigs transgenic for ELOVL4 should lead to new insights into lipid metabolism in photoreceptor cells and may reveal a novel pathway in the pathogenesis of macular degeneration.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Small Research Grants (R03)
Project #
5R03EY013978-03
Application #
6894004
Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Dudley, Peter A
Project Start
2003-05-01
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2007-04-30
Support Year
3
Fiscal Year
2005
Total Cost
$146,500
Indirect Cost
Name
North Carolina State University Raleigh
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Estrada, Jose L; Collins, Bruce; York, Abby et al. (2008) Successful cloning of the Yucatan minipig using commercial/occidental breeds as oocyte donors and embryo recipients. Cloning Stem Cells 10:287-96
Sommer, Jeffrey R; Collins, E Bruce; Estrada, Jose L et al. (2007) Synchronization and superovulation of mature cycling gilts for the collection of pronuclear stage embryos. Anim Reprod Sci 100:402-10
Estrada, Jose; Sommer, Jeffrey; Collins, Bruce et al. (2007) Swine generated by somatic cell nuclear transfer have increased incidence of intrauterine growth restriction (IUGR). Cloning Stem Cells 9:229-36