STRA6 and Ocular Vitamin A Homeostasis

ABSTRACT The fat-soluble vitamin A (all-trans-retinol) is distributed in the body to maintain retinoid signaling in peripheral tissues and vision in the eyes. This transport occurs via an extrinsic pathway for the distribution of dietary vitamin A in the form of retinyl esters in chylomicrons and an intrinsic pathway for the distribution of vitamin A from hepatic stores bound to the retinoid binding protein RBP4. Cellular uptake of vitamin A from these two transport modes is facilitated by lipoprotein lipase and by the RBP4 receptor STRA6 (Stimulated by Retinoic Acid 6), respectively. Disrupted vitamin A transport is a serious health problem and is associated with blinding diseases ranging from night blindness to complex ophthalmic syndromes. We propose to study the etiology of ocular diseases states that are associated with perturbed ocular vitamin A uptake homeostasis by comparing the eyes of STRA6-deficient and that of control mice. In Aim 1, we will examine the role of STRA6 in the functioning of the outer blood-retinal barrier. We will study whether ocular vitamin A deficiency in Stra6 knockout mice impairs the structural integrity and functioning of this barrier. Additionally, we will examine whether retinoid signaling regulates the expression of key components of both the outer blood-retina barrier in mice and human retina pigment epithelium cells derived from inducible pluripotent stem cells. In Aim 2, we will use Stra6 knockout mice to analyze the consequences of imbalances in ocular retinoid concentrations on rod and cone photoreceptor function and ultrastructure. We will generate novel transgenic mouse lines to examine the competition between rods and cones for limited chromophore in the STRA6-deficient eyes. This research will address the question whether the STRA6/RBP4-dependent transport system is an adaption to the high chromophore demand from rod photoreceptors. In Aim 3, we will study whether manipulation of the extrinsic pathway can rescue cone and rod photoreceptor function in STRA6-deficiency and whether the STRA6/RBP4 uptake system provides selectivity for the uptake of canonical retinoids. Collectively, our proposed studies will advance knowledge about ocular vitamin A homeostasis by elucidating its mechanisms in the physiological state and by studying the consequences of its loss-of-function in disease states.