Indeed, such an approach has been emphasized in previous reviews (Ambati et al., 2003a, Bird, 2010, Patel and Chan, 2008, Rattner and Nathans, 2006 and Zarbin, 2004). Instead, since diverse etiologies may contribute to an AMD phenotype, we advance three models of disease mechanism that emphasize critical, nonredundant effector pathways. In each of these models, the RPE is the fulcrum of AMD pathogenesis. In general, although interindividual heterogeneity exists, RPE dysfunction and atrophy precedes the latter stages of AMD (GA or CNV). The RPE integrates numerous stimuli to define its own health, while also click here receiving and broadcasting signals to and from the retinal microenvironment. The capacity of the

RPE to modulate diverse pathways of AMD pathogenesis can be gleaned from RNA transcriptome analyses of human AMD donor eyes (Booij et al., 2010 and Newman et al., 2012) and in vitro RPE cells (Strunnikova et al., 2010). Importantly, human AMD samples display significant interindividual variation in RPE transcript expression, which supports the concept that heterogenic stress responses underlie a categorical AMD phenotype. Genome-wide www.selleckchem.com/products/a-1210477.html stress-response transcriptome and

proteome assays have begun to catalog the effect of specific AMD-associated stresses (Kurji et al., 2010), and age-related changes in retinal molecular composition (Cai and Del Priore, 2006 and Glenn et al., 2011) on whole-genome RPE gene expression. If these types of experimental approaches are applied to a multitude of AMD-associated stresses, the pooled results of these first studies could reveal common protective and deleterious RPE gene responses and would also help clarify the key molecular drivers of disease. Subsequently, the manipulation of critical pathways in stress-function assays and animal

models of AMD could create new avenues of therapeutic strategy and augment existing knowledge garnered from focused investigations of specific pathways or sets of genes. An important route of communication and recurring theme in AMD pathology is the crosstalk of RPE with immune and vascular systems. This “immunovascular axis” drives CNV; however, whether this network modulates RPE cell viability is less clear. Although the vitality of the RPE cell is paramount to retinal health, it is also true that perturbations in other tissues, for example, the choroid, Bruch’s membrane and photoreceptors, are important burdens on the retinal microenvironment. Nevertheless, the critical event in AMD pathogenesis, from which there is no return, is RPE dysfunction and degeneration. Our first of three paradigms of AMD molecular pathogenesis is an integrated view of CNV that is supported by an abundance of successful therapeutic efforts in human and animal models. Figure 2 details the molecular mechanisms of CNV pathogenesis. As will be discussed, the RPE response to heterogeneous stressors is an integral process in CNV.