Proteomic Trajectory Mapping of Retinopathy of Prematurity

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DESCRIPTION (provided by applicant): The vertebrate retina undergoes drastic transformation after birth into the fully functional adult form. During postnatal development the proliferation of retinal cells and network formation in the neural retina take place. Healthy development is crucial to the full manifestation of retinal function in the adult stage. Exposure of premature infants to hyperoxia, upon returning to a normal oxygen level (normoxia), causes retinopathy. This disease is called "retinopathy of prematurity" or ROP. ROP is triggered by the retinal neovascularization induced by the normoxia after the hyperoxic condition is removed, and the consequent ophthalmologic complications takes place including bleeding, invasion of new vessels to outside of the retina, and finally retinal detachment. The rodent model of Oxygen Induced Retinopathy (OIR) is widely utilized as an experimental animal model for human ROP. Our long term goal is to understand the molecular pathways underlying the retinopathy using the mouse model of OIR and to use the model to establish an assay protocol to evaluate drugs that would suppress the progress of ROP. For this purpose we use a novel technology called "Proteomic Trajectory Mapping" that has been developed by the PI's group. Proteomic trajectory mapping describes the expression of each retinal protein along the developmental time axis. We hypothesize that ROP will be manifested in the alterations of the proteomic trajectories and certain drugs will reverse the alteration process. To evaluate this hypothesis, we will use the mouse model of OIR and propose the following three aims in the two year period. Specific Aim 1: To define proteomics trajectories in the mouse model of OIR in comparison to normal retinal development. Specific Aim 2: Expression of the key proteins and genes underlying the retinal development and its alteration in OIR will be investigated both at the protein level by western blot and at the mRNA level by real- time PCR. Specific Aim 3: Cellular localization of six transcription factors/regulators which have been identified by our proteomics experiments will be investigated by immunohistochemistry in both normal and OIR retinas. Achievement of these aims will give us crucial information on the molecular pathways that are involved in the pathogenesis of ROP. The results will contribute significantly to the development of drugs for the treatment of ROP and other related retinal diseases.