Macular Degeneration Research - Current Award
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Aparna Lakkaraju, Ph.D.
Board of Regents of the University of Wisconsin System
Madison, WI
Title: Apolipoprotein E And Cholesterol Lowering Drugs In Age-Related Macular Degeneration
Non-Technical Title: Cholesterol homeostasis and age-related macular degeneration
Duration: April 1, 2009 - March 31, 2012
Award Type: Standard
Award Amount: $100,000 |
Summary:
The specific aims outlined in this proposal will provide a cell biological understanding of the role of a protein called apolipoprotein E and the regulation of cholesterol levels in the retinal pigment epithelial (RPE) tissue of the eye). We will also investigate the potential of two promising drugs, statins and PPARgamma agonists, which are currently being used to treat, respectively, atherosclerosis and diabetes. These drugs will be tested for their ability to maintain cholesterol balance in the RPE. |
Details:
It is now becoming increasingly apparent that many chronic age-related diseases such as atherosclerosis, Alzheimer's disease, and macular degeneration share common pathological characteristics. One such characteristic is the abnormal metabolism of cholesterol as a result of defective functioning of proteins involved in this process. For example, genetic variations in apolipoprotein E (ApoE), which transports cholesterol into and out of the cell, have been associated with Alzheimer's disease and age-related macular degeneration (AMD). Another protein called sterol regulatory element binding protein (SREBP) controls the levels of the low density lipoprotein (LDL) receptor on the cell surface and the synthesis of new cholesterol. Thus, SREBP helps control the amount of cholesterol in the cell.
Our goal is to understand the functioning of ApoE and SREBP in cells of the retinal pigment epithelium because previous data from our lab shows that these cells lose the ability to handle cholesterol under conditions that mimic those found in AMD. Our results have the potential to ascertain whether drugs like statins, which activate SREBP and are widely used to treat atherosclerosis, can also help maintain proper cholesterol metabolism in the retinal pigment epithelial (RPE), which may, in turn, help treat or prevent AMD.
In this project, we aim to:
1. investigate the role of ApoE in the RPE, especially with regard to how genetic variations in this protein affect its function; and
2. investigate the activation of SREBP and regulation of the LDL receptor and statin function in the RPE.
Progress Updates:
Our aim is to clarify the role of apolipoprotein E in cholesterol transport in the retinal pigment epithelium (RPE - the cell layer that nourishes the light-detecting cells), because previous data from our lab shows that these cells lose the ability to handle cholesterol under conditions that mimic those found in macular degeneration. In the past year, we have examined the sub-cellular localization of apolipoprotein E in RPE cells by confocal microscopy (a technique that reconstructs 3D-images of the landscape inside and outside of cells). Surprisingly, we found that a significant portion of this protein is found in late endosomes (cell protein-processing sacs).
Our previously published results showed that the major component of the age-pigment lipofuscin, A2E (that is deposited in the retina of individuals with macular degeneration), causes cholesterol accumulation in late endosomes in RPE cells. The fact that apolipoprotein E is also found in the same intracellular compartment in these cells raises the intriguing possibility that this transporter co-operates with other cholesterol transporters present in late endosomes and helps to shuttle cholesterol to various destinations within the cell. We are now investigating the roles of different isoforms of apolipoprotein E in its subcellular localization and in cholesterol transport in the RPE. (An isoform is a different form of the same protein created by either genetic or post-expression processing).
