The long term objectives of the applicant are to gain insight into the interactions of oxygen and capillary endothelial cells and to apply this knowledge to a better understanding of the pathophysiology of retinopathy of prematurity (ROP), and to the development preventive and therapeutic modalities. ROP is a serious vasoproliferative disorder of premature infants in which retinal capillary cells grow at an extremely accelerated rate. Mechanisms controlling this phenomenon are not well understood, but oxygen tension most likely plays an important role. Phase I experiments focus on the regulation of bFGF, TGF-beta, PA, PAI-1, and type IV collagenase by oxygen first in adrenal capillary cells, then in retinal capillary cells.
Specific Aim 1 looks at the effects of varying levels of oxygen on capillary cell growth and proliferation. The second Specific Aim will investigate changes in bFGF, TGF-beta, PA, PAI-1, and type IV collagenase production by capillary endothelial cells under varying oxygen conditions. Phase II experiments include the third Specific Aim which looks at cell-cell interactions between capillary endothelial cells and pericytes. Changes in growth factors or molecules modulating growth factor activity will be assessed. The fourth Specific Aim will investigate the responsiveness of capillary endothelial cells to exogenous bFGF and TGF-beta under different oxygen tensions. Finally, the fifth Specific Aim will investigate the effects of neutralizing antibodies on the in vivo kitten model of oxygen-induced retinopathy. The overall hypothesis of these studies is that oxygen regulates angiogenesis, with hypoxia being a stimulus and hyperoxia being an inhibitor. Phase I investigations will provide valuable training with methods to study the interactions of oxygen, endothelial cells, and growth factors. These can ultimately be used in Phase II investigations testing to preventive and therapeutic modalities for ROP. Results of the in vitro studies will be applied to the kitten model of oxygen-induced retinopathy for in vivo animal studies and, ultimately, to studies in the clinical setting.
| Nunes, I; Higgins, R D; Zanetta, L et al. (2001) c-abl is required for the development of hyperoxia-induced retinopathy. J Exp Med 193:1383-91 |
