Metabolic stress appears to be a factor in late-onset retinal degeneration in transgenic mice. We discovered retinal degeneration and loss of vision in mice rendered chronically hypoglycemic from a null mutation of the glucagon receptor gene, Gcgr, or of the prohormone convertase 2 gene, PC2. Gcgr-/- and PC2-/- mice show the first signs of degeneration and loss of acuity at about 10 months of age and become functionally blind by about 14 months. The underlying molecular and cellular mechanisms are not known, but the availability of glucose appears to be critical.
Specific aims are to investigate:
Aim 1 : Late onset retinal degeneration in hypoglycemic mice.
Aim 2 : Cellular and molecular mechanisms underlying late-onset retinal degeneration.
Aim 1 proposes a rigorous, systematic study of the following properties of Gcgr and PC2 null mice: retinal/RPE anatomy, retinal and photoreceptor sensitivity, retinal cell distribution and cell death, and visual function. We will track retinal degeneration in living mice using new, innovative methods: optical coherence tomography (OCT) to image retinal structures with 3.5 (m resolution and behavioral methods to measure visual function.
Aim 2 proposes to test for changes in cytosolic/organellar pH from the downregulation of V-ATPase in Gcgr-/- mice.
Aim 2 will also test the sensitivity of retinas to the combined stress of hypoglycemia and hypothermia, and test the efficacy of supplemental diets and antioxidants in rescuing vision of Gcgr-/- and PC2-/- mice. Potential medical benefits: (1) identification of metabolic stress as a factor in late-onset retinal degeneration, (2) development of a transgenic mouse model for retinal degeneration resulting from the null mutation of a gene, Gcgr, not expressed in the retina, (3) use of innovative methods for noninvasive measures of the retina and vision in mice, and (4) potential for yielding insights about causes of late-onset retinal degeneration in humans.
| Khan, Mukhtar I; Barlow, Robert B; Weinstock, Ruth S (2011) Acute hypoglycemia decreases central retinal function in the human eye. Vision Res 51:1623-6 |
| Petrs-Silva, Hilda; Dinculescu, Astra; Li, Qiuhong et al. (2011) Novel properties of tyrosine-mutant AAV2 vectors in the mouse retina. Mol Ther 19:293-301 |
| Solessio, Eduardo; Umino, Yumiko; Cameron, David A et al. (2009) Light responses in rods of vitamin A-deprived Xenopus. Invest Ophthalmol Vis Sci 50:4477-86 |
| Ding, Xi-Qin; Harry, Cynthia S; Umino, Yumiko et al. (2009) Impaired cone function and cone degeneration resulting from CNGB3 deficiency: down-regulation of CNGA3 biosynthesis as a potential mechanism. Hum Mol Genet 18:4770-80 |
| Petrs-Silva, Hilda; Dinculescu, Astra; Li, Qiuhong et al. (2009) High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. Mol Ther 17:463-71 |
| Umino, Yumiko; Solessio, Eduardo; Barlow, Robert B (2008) Speed, spatial, and temporal tuning of rod and cone vision in mouse. J Neurosci 28:189-98 |
| Kim, Ki Hean; Puoris'haag, Mehron; Maguluri, Gopi N et al. (2008) Monitoring mouse retinal degeneration with high-resolution spectral-domain optical coherence tomography. J Vis 8:17.1-11 |
| Everhart, Drew; Stachowiak, Ana; Umino, Yumiko et al. (2008) Loss of visual and retinal function in light-stressed mice. Adv Exp Med Biol 613:157-64 |
| Alexander, John J; Umino, Yumiko; Everhart, Drew et al. (2007) Restoration of cone vision in a mouse model of achromatopsia. Nat Med 13:685-7 |
| Umino, Yumiko; Frio, Bridget; Abbasi, Maryam et al. (2006) A two-alternative, forced choice method for assessing mouse vision. Adv Exp Med Biol 572:169-72 |
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