Vitamin A metabolism, vascular inflammation, retinal degeneration, and diabetic retinopathy

1. Serum retinol-binding protein (RBP4) is the sole specific transport protein for Vitamin A (retinol) in the blood. Elevation of RBP4 contributes to the development of insulin resistance and type 2 diabetes.  Patients with diabetes have an increased risk for developing cardiovascular disease and other vascular complications, such as diabetic retinopathy.  Recent clinical studies have found that patients with vascular diseases, including hypertension, atherosclerosis, stroke, as well as diabetic retinopathy, have increased levels of RBP4.  The significance of these clinical correlations is unclear, but it raises the possibility that RBP4 may contribute to the pathogenesis of cardiovascular disease and diabetic retinopathy.  Chronic endothelial inflammation is an underlying causative factor in the development and progression of both cardiovascular disease and diabetic retinopathy.  Dr. Farjo and colleagues have shown that elevation of RBP4 induces inflammation in primary human retinal capillary endothelial cells (HRCEC) and human umbilical vein endothelial cells (HUVEC) by stimulating expression of pro-inflammatory molecules involved in leukocyte recruitment and adherence to endothelium.  Moreover, her group has demonstrated that RBP4 induces inflammation in endothelial cells by a novel mechanism, which is unrelated to its role as a carrier of retinoids, and involves activation of NADPH oxidase and NF-kB, two key signaling molecules known to be involved in the induction of endothelial inflammation during diabetic retinopathy and atherosclerosis.  Dr. Farjo’s lab is now focused on discovering more about the mechanisms of RBP4-induced endothelial inflammation and determining how elevation of RBP4 affects vascular inflammation and retinal physiology using transgenic mice that over-express RBP4. This research could lead to new diagnostic and therapeutic approaches to predict and reduce morbidity and mortality in patients with cardiovascular disease and diabetes. 

2. Patients with macular degeneration experience a loss of central field vision that progressively worsens with age and can lead to complete blindness.  Age-related macular degeneration (AMD) is the leading cause of visual disability in the United States, currently affecting more than 1.75 million citizens.   Age is the most significant risk factor for AMD, as it primarily occurs in people of age 50 years or older, while people over the age of 70 years have a 30% chance of developing symptoms of AMD. The incidence of AMD is expected to nearly double by the year 2020 due to the rapidly aging U.S. population. In addition, a juvenile form of macular degeneration known as Stargardt disease (STGD) affects 1/10,000 people and causes vision loss as early as 6 years of age.  Currently, there is no effective preventative therapy for patients with STGD or early-stage AMD (“dry-AMD”).  AMD and STGD are both initiated and perpetuated by the accumulation of toxic vitamin A derivatives in the retina, thus reducing the formation of toxic Vitamin A derivatives could prevent vision loss in both diseases.  Dr. Farjo’s lab is focused on developing new biologically-derived molecules designed to reduce vitamin A uptake into the retina and thereby inhibit the generation of toxic Vitamin A derivatives. This research could serve as the basis for the development of a safe and effective therapeutic for the treatment of STGD and early-stage AMD, fulfilling an unmet and critical need.

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