Massive periretinal proliferation (MPP) is a serious clinical problem characterized by cell proliferation, membrane formation, and retinal detachment. The early biochemical and physiological changes which accompany MPP are poorly defined. Marked increases in ornithine decarboxylase (ODC) activity and rapid accumulation of the tissue polyamines putrescine, spermidine, and spermine are characteristically associated with rapid cell growth. In turn, S-adenosylmethionine (SAM) and its metabolites are required for polyamine biosynthesis. In this proposal, we will test the hypothesis that increased ODC activity followed by increased polyamine content may play an essential role in MPP. The trauma model in the rabbit will be utilized to study ODC activity, polyamine levels, and SAM and its metabolites associated with MPP at various stages. These biochemical parameters will be measured in a normal rabbit retina and compared to a fellow retina during development of MPP. The primate model, a more clinically relevant model, will be used in the study of the relationship between MPP and ODC activity following the studies in the rabbit. Whether induction of ODC activity and increased polyamine levels are requirements for retinal cellular proliferation must be determined. Recent development of a potent biochemical mechanism-based irreversible inactivator of ornithine decarboxylase, DL-alpha-difluoromethylornithine (alpha-DFMO), has rapidly advanced research on the role of polyamines in cell growth and differentiation in recent years. If induction of ODC activity is a requirement for cellular proliferation on the retina and into the vitreous, then alpha-DFMO (or other analogues) may be utilized to prevent the abnormal retinal cell growth leading to retinal detachment. Inactivation of retinal ODC with this compound will be accomplished using the appropriate route of administration. The time course of ODC inactivation along with polyamine levels will be determined. Whether cessation of ODC activity will prevent the cellular proliferation leading to retinal detachment will be ascertained. Altogether, this body of work will define the importance of ODC and polyamines in the process of MPP.
| Wong, C G; Naripthaphan, P; Renardel de Lavalette, V (1987) Ornithine decarboxylase activity in rabbit retina following treatment with alpha-difluoromethylornithine. Biochem Pharmacol 36:4325-9 |
