• Holmes, Jonathan M (PI)

Project: Research project

Project Details


DESCRIPTION (Adapted from the applicant's abstract): Retinopathy of prematurity
(ROP) is a blinding disease of premature infants resulting from development of
abnormal blood vessels in the immature retina. It has been well established
that excess oxygen is an important causative factor in the pathogenesis of ROP.
Nevertheless, despite the more careful use of oxygen, the incidence of ROP is
increasing in the United States. In addition, current treatments for severe ROP
fail to prevent blindness in a large proportion of infants. Therefore, further
research into the pathogenesis of ROP is critical to increase our understanding
of the disease and to develop new methods of prevention and treatment. Infants
who never experience hyperoxia (e.g., those with congenital heart disease) may
also develop ROP. For these infants in particular, and for premature neonates
in general, systemic acidosis has been implicated as a risk factor in the
development of ROP. A new neonatal animal model has been developed that allows
study of metabolic acidosis and retinal neovascularization. The investigator
has confirmed that metabolic acidosis alone leads to preretinal
neovascularization in the retina of immature animals, and has termed this model
"metabolic acidosis-induced retinopathy" (MAIR). Using this model, the
investigator proposes to characterize the effect of acidosis on the immature
retina and investigate biochemical and molecular mechanisms. These studies may
lead to new avenues of prevention and treatment of ROP. The primary hypothesis
for this series of experiments is that: "acidosis is a risk factor for ROP in
human neonates." This leads to the following secondary hypotheses that will be
tested in the MAIR model, which is that: (1) a dose-response relationship
exists between the extent of metabolic acidosis and the severity of retinopathy
in the neonatal rat model; (2) neovascularization in the acidotic model is
mediated by down-regulation followed by up-regulation of one or more growth
factors including vascular endothelial growth factor (VEGF), basic fibroblast
growth factor (bFGF) and insulin-like growth factor 1 (IGF-1); and (3) the
retinopathy can be prevented by reversal of acidosis.
Effective start/end date2/1/001/31/06


  • Medicine(all)