Genetic Susceptibility to the Murine Model of Retinopathy of Prematurity: Identification of a Novel Role of Tyrosinase in Retinal Angiogenic Regulation

Retinopathy of Prematurity (ROP) is a major cause of vision loss in the pediatric population. A growing body of evidence suggests that a heritable component contributes to risk of disease development. Identification of genes that modify disease susceptibility may provide a means to determine which children are at higher risk of developing ROP, as well as identify potential pharmacological targets to prevent progression of disease to vision-threatening stages. Using the murine model of ROP, oxygen-induced retinopathy (OIR), we developed a mapping cross that identified 2 quantitative trait loci associated with resistance to OIR. This work also found an association between albinism and reduced retinal avascular area. As albinism in our study was caused by loss of function of Tyrosinase (Tyr), we confirmed that function of this gene is associated with increased risk of OIR susceptibility using the Tyr-null murine strain. Tyr function was also found to inhibit endothelial progenitor cell (EPC) proliferation, mobilization, and recruitment to the retina. Subsequent studies exploring the mechanism of these findings demonstrated that Tyr function contributes to peripheral production of dopamine, and that dopamine inhibits retinal revascularization and EPC recruitment to the retina by signaling through the D1-like family of receptors. A time course study examining the number of EPCs in bone marrow, blood, and retina using both Tyr-null and wild-type mice identified patterns of proliferation, mobilization, and recruitment associated with more and less successful response to OIR. This study additionally suggested that retinal revascularization and associated EPC response in this model begins prior to the customary time point of P12, which has important implication for future studies seeking to modify EPC contribution to this disease. A microarray analysis comparing transcriptional regulation between strains of mice known to be susceptible and resistant to OIR identified additional pathways that also contribute to disease susceptibility, and identified several areas of interest for future experiments. Together, these studies describe a novel role of dopaminergic signaling in retinal vascularization and identify potential mechanisms that contribute to susceptibility to ROP. &#8195

The genetic control of avascular area in mouse oxygen-induced retinopathy

Purpose: The C57BL/6ByJ and BALB/cByJ inbred strains of mice are, respectively, susceptible and resistant to oxygen-induced retinopathy (OIR). The purpose of this work was to investigate the genetic control of the retinal avascular area in mouse OIR using a mapping cross. Methods: The central retinal avascular area was measured on postnatal day 16 (P16) in C57BL/6ByJ, BALB/cByJ, 101 (C57BL/6ByJ x BALB/cByJ)F2, and 116 (BALB/cByJ x C57BL/6ByJ)F2 mice that had been subjected to the OIR protocol. A genome-wide scan was performed of selected albino and non-albino mice to determine quantitative trait loci associated with weight and avascular area. Results: C57BL/6ByJ mice had significantly larger avascular areas than BALB/cByJ ones. Albino mice of the F2 generation had smaller avascular areas than the non-albino mice. Genotyping was performed at 856 informative single nucleotide polymorphisms approximately evenly distributed across the genome from each of 85 selected F2 mice. Weight, sex, and the paternal grandmother were found to act as additive covariates associated with the avascular area on P16; mapping analyses that used a model incorporating these covariates found a quantitative trait locus on chromosome 7 related to avascular area. Mapping analyses that used a model that did not incorporate covariates found a quantitative trait locus on chromosome 9 related to avascular area. A quantitative trait locus for bodyweight on P16 was mapped to chromosome 5. Conclusions: The retinal avascular area in the mouse OIR model is under genetic control. Revascularization in OIR is related to the weight, strain of paternal grandmother, sex, and albinism. Our data support the existence of a quantitative trait locus on chromosome 5 that influences weight after exposure to hyperoxia, as well as quantitative trait loci on chromosomes 7 and 9 that modify susceptibility to OIR

Relationship Between Cerebral Amyloid Burden and OCT Changes in Preclinical Alzheimer's Disease

Preclinical Alzheimer's disease (AD) is an early stage of AD with increased cerebral amyloid burden, measured either by cerebral spinal fluid (CSF) amyloid markers or positron imaging tomography (PET). Our previous study demonstrated enlargement of the foveal avascular zone (FAZ) of eyes from preclinical AD patients compared to controls, a feature that is stable at follow-up after 3 years. Here we present additional analysis of relationships between severity of cerebral amyloidosis and changes in retinal structure and vascularity

Optical Coherence Tomography Angiography Findings in Pre-Clinical, Biomarker Positive Alzheimer's Disease

Alzheimer's disease (AD) is marked by slowly progressive memory loss, behavioral changes, and deterioration of executive function. Approved treatments prevent further neurodegeneration, but symptoms of AD only become apparent after irreversible loss has already occurred. Optical coherence tomography (OCT) and OCT angiography (OCTA) are noninvasive imaging techniques that allow analysis of retinal and microvascular anatomy. Here, we use OCT and OCTA technology to compare retinal architecture and vascularization between individuals with pre-clinical, biomarker positive AD and biomarker-negative age-matched controls