Aberrant RPE mTORC1 signaling in dysregulation of choroid homeostasis

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The overall goal of the project is to delineate the cellular and molecular mechanisms that link dysfunction of the retinal pigment epithelium (RPE) to degeneration of the choriocapillaris (CC). Choroidal atrophy is an early pathological change in age-related macular degeneration (AMD), a leading cause of blindness in elderly people. The RPE produces a number of trophic factors that support the structural integrity of the choroidal vasculature. Aging and age-related degeneration can interfere with the functional interactions between the RPE and CC. The underlying disease mechanisms are largely unclear. We found that the mouse model of RPE-specific overactivation of the mechanistic target of rapamycin complex 1 (mTORC1) recapitulated many of the clinical features of CC dropout. RPE cells with high mTORC1 activity had increased release of angiopoietin 2 (ANGPT2), a vascular destabilizing factor that is usually produced by endothelial cells (ECs) and exerts autocrine effects on its receptor TIE2. We further identified that the secretion of ANGPT2 from RPE was likely mediated by the upregulation and activation of a phosphoprotein DARPP-32. Based on these novel findings, we hypothesize that ANGPT2 production and secretion from the RPE contribute to the degeneration of choroid under pathological conditions that involve dysregulated mTORC1 signaling. The hypothesis will be tested in three specific aims. Aim 1 is to determine whether mTORC1 activation in the RPE will stimulate ANGPT2 secretion via DARPP-32-dependent mechanisms. Aim 2 is to examine whether ANGPT2 can regulate the function of choroidal ECs via TIE2-dependent or independent pathways. Aim 3 is to determine whether genetic knockout of ANGPT2 in the RPE, or AAV-mediated overexpression of ANGPT2 will influence the CC atrophy in the mouse model of mTORC1 hyperactivation. The results from these studies will provide insights on how the AMD-related signaling events in the RPE impact its support to the CC. The newly identified ANGPT2-TIE2 axis between the RPE and choroidal ECs can be a molecular pathway for the therapeutic intervention of choroidal atrophy.