The fat soluble vitamin A (all-trans-retinol) must be distributed in the body to maintain retinoid signaling in the periphery and vision in the eyes. This transport occurs via two overlapping pathways: vitamin A from the diet is distributed in the form of retinyl esters in chylomicrons and vitamin A from hepatic stores is distributed bound to the retinol binding protein RBP4 (holo- 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. Deficiency of vitamin A transport is a serious health problem and associated with blinding diseases. We have generated a STRA6-deficient mouse model. As demonstrated by our recent studies and preliminary data, ocular retinoid concentrations can be manipulated in this mouse model in by dietary intervention. Control mice can maintain their ocular retinoids under this condition. Thus, this mouse model presents a unique animal model to study the biochemistry of vitamin A and physiology of transport and the consequences of its pathological impairment in certain disease states.
In Aim 1 we will analyze the role of the RBP4 receptor in leveling ocular vitamin A as a bidirectional transporter in live animals.
In Aim 2, we will use the Stra6 knockout mouse to analyze the consequences of imbalances in ocular retinoid concentrations for ocular health. By combining the knowledge of aberrant genetic pathways with imaging techniques and biochemical analyses, we will connect the transcriptome to the phenotype of the eyes in the vitamin A deficient and sufficient states.
In Aim 3 we will study whether disturbances in ocular vitamin A metabolism is a characteristic of the etiology of diabetic retinopathy and will test whether reduced ocular vitamin A concentration can alleviate pathological consequences of this disease in the mouse eyes. Collectively, our proposed studies will advance our current knowledge about the biology of ocular vitamin A homeostasis. Our studies will describe the molecular and biochemical framework through which ocular vitamin A homeostasis is maintained in the physiological state and decipher the pathological consequences of perturbed ocular vitamin A import and export in disease states.

Public Health Relevance

The membrane protein STRA6 facilitates vitamin A uptake into the eyes. Emerging evidence indicates that disturbance in this process is associated with inherited and chronic disease. Defining the molecular and biochemical foundation of ocular vitamin A import and export is desirable to assist the development of therapeutic intervention against blinding disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY028121-03
Application #
9982937
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Neuhold, Lisa
Project Start
2018-08-01
Project End
2023-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106