The overall objective of this proposal is to determine the role of SHP-1, a cytoplasmic protein-tyrosine phosphatase, in the regulation of homeostasis in the retina. We hypothesize that SHP- 1 regulates the phagocytic functions of the RPE and the level of activation of phagocytic cells within the retina. The viable motheaten mutation results in severe SHP- 1 deficiency and provides a critical tool for elucidating the mechanism of photoreceptor loss in retinal degeneration, as well as regulatory mechanisms of normal phagocytosis in the retina.
The specific aims are (1) to characterize retinal degeneration in viable motheaten mice. Determining the development and temporal progression of retinal degeneration will allow us to distinguish primary effects from secondary insults. Morphologic and immunocytochemical analysis will delineate the interactions of phagocytes and other cell populations in the retinal degeneration of viable motheaten mice. (2) To localize and identify the interactions of SHP- 1 in the retina. This will determine if SHP- 1 functions as a critical regulatory molecule in the maintenance of retinal homeostasis. Immunohistochemistry, immunoprecipitation and Western blot analysis will demonstrate the spatial localization and molecular interactions of SHP-1 within the retina. (3) To determine the role of melanin in the progression of retinal degeneration. The absence of melanin is postulated to accelerate the progression of retinal degeneration in viable motheaten mice. Generation of albino viable motheaten mice on the congenic C57BL/6J-tytc2j strain background will determine if the absence of melanin accelerates the progression of retinal degeneration in viable motheaten mice. Ultrastructural detection of lipid peroxides will demonstrate that accelerated progression is associated with increased lipid peroxidation in the RPE. Such determinations will test the hypothesis that SHP- 1 is a critical signaling molecule necessary for the normal phagocytic function of the RPE.
| Lyons, Bonnie L; Smith, Richard S; Hurd, Ron E et al. (2006) Deficiency of SHP-1 protein-tyrosine phosphatase in ""viable motheaten"" mice results in retinal degeneration. Invest Ophthalmol Vis Sci 47:1201-9 |
| Ueno, Motonobu; Lyons, Bonnie L; Burzenski, Lisa M et al. (2005) Accelerated wound healing of alkali-burned corneas in MRL mice is associated with a reduced inflammatory signature. Invest Ophthalmol Vis Sci 46:4097-106 |
