Mechanism of SR-BI-Mediated Macular Carotenoid Transport
Co-Principal InvestigatorsPaul S. Bernstein, MD, PhD University of Utah
CollaboratorThierry Huby, PhD Sorbonne University
Supplementation of macular carotenoids can protect human retina against age-related macular degeneration (AMD), a leading cause of blindness in the USA. Carotenoids are a class of mainly yellow, orange, or red pigments that provide color to plants and natural organisms, and serve as vital nutrients for human vision. Humans do not synthesize carotenoids and have to obtain them from diets; therefore, it is important to understand the relevant mechanism of macular carotenoid transport. However, that is still unknown because there has been no appropriate small animal model that is capable of accumulating carotenoid in their retinas. Recently, we discovered that mice deficient in β-carotene oxygenase 2 (BCO2), a carotenoid cleavage enzyme, can deposit carotenoid in their retinas, and we plan to use this mouse model to study the biochemical mechanism underlying macular carotenoid transport mediated by a protein known as scavenger receptor B1 (SR-B1) a critical carotenoid transporter. The results may lead to new treatments and therapies to prevent AMD using carotenoid supplementation.
Carotenoids can reduce approximately 40 percent of the risk of AMD, but humans do not synthesize carotenoids and have to obtain them from diets. Therefore, it is important to understand the mechanism of macular carotenoid transport.
Our goal is to understand the mechanism of scavenger receptor BI (SR-BI)-mediated macular carotenoid transport.SR-BI has long been thought to be the critical protein responsible for the uptake of macular carotenoids from the bloodstream to the retina; however, until now, this biochemical pathway has been difficult to approach because there have been no appropriate animal models for this study. Our recent discovery of “macular pigment mice” that can reproducibly take up carotenoids into the retina finally allows investigation into this problem.
In Specific Aim I, using our unique macular pigment mice which can accumulate carotenoids in their retinas, we are defining whether SR-BI is the critical protein to transport carotenoids from the bloodstream to the retina. The SR-BI gene is deleted specifically from the retinal pigmented epithelium (RPE) cells of the macular pigment mice. Once we have these knockout mice, we will feed them carotenoids for one month. If no carotenoid is detected in the retina, it will demonstrate that SR-BI is the critical carotenoid transporter.
In Specific Aim II, we are investigating the molecular mechanism of SR-BI- mediated carotenoid transport. Using cell culture assays, we are exploring whether carotenoids enter RPE cells through a cholesterol tunnel found in the SR-BI protein, and we also are testing whether SR-BI needs a protein partner to facilitate carotenoid transport.
In Specific Aim III, we are examining if there are additional proteins involved in macular carotenoid transport. Using surface plasmon resonance (SPR) spectroscopy, we are screening the potential protein candidates. They should be able to bind the macular carotenoids lutein and zeaxanthin more tightly than other carotenoids.
Completion of our proposed research will facilitate our understanding of macular carotenoid transport, offering new treatments and therapies to prevent AMD and other human eye disease using carotenoids.