The Role of an Immune Cell Attractant In A Blinding Disease

Goldis Malek, PhD
Duke University (Durham, NC)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to December 31, 2017
Disease:
Macular Degeneration
Award Amount:
$160,000
Grant Reference ID:
M2015421
Award Type:
Standard
Award Region:
US Southeastern

This grant is made possible by a gift made in memory of Carolyn K. McGillvray. Recipient of The Carolyn K. McGillvray Award.

Goldis Malek, PhD

The Role Of A Macrophage Chemotactic Factor In AMD

Summary

Age-related macular degeneration (AMD) is a devastating disease resulting in blindness in the elderly. Though what causes it is still unknown, we know that the immune system is involved. The experiments in this study are designed to address the following question: What is the role of a specific factor called osteopontin that may be responsible for recruiting immune cells to eye in the development and progression of AMD? The answer may result in identification of a future target for therapy.

Details

Inflammation and in particular immune cells called macrophages and monocytes, are associated with all clinical stages of macular degeneration (AMD). How these immune cells contribute to progression of vision loss is unknown. With funding from BrightFocus Foundation, our lab is investigating the hypothesis that increased levels of a newly identified macrophage chemotactic factor correlates with progression and severity of AMD. Our study design calls for investigating the biological and physiological function of this chemotactic factor in cells that are vulnerable in AMD, including retinal pigment epithelial (RPE) cells that serve as nurse cells to the overlying retina; choroidal endothelial cells that stabilize the outer retinal vasculature; and monocytes, which are circulating immune cells capable of infiltrating and residing within the retinal tissue. Currently we are examining expression levels of this factor in eye tissue samples and blood serum from donor eyes with different stages of AMD. We are also determining the impact of this factor on the inflammatory state of macrophages. In other words, we are asking the question; Do high levels of this chemotactic factor induce a pro- or anti-inflammatory phenotype in macrophages? Finally, using mouse models, we are examining if high levels of this chemotactic factor can directly impact phenotypes characteristic of different clinical sub-types of AMD, including accumulation of sub-RPE deposits (drusen phenotype), and RPE cell loss (geographic atrophy phenotype). This study is the first to examine the role of this factor in AMD onset and progression utilizing a combination of cell culture models, mouse models, and human tissue samples. The results of these experiments will further clarify the contributions of this factor to AMD progression. Additionally by virtue of investigating its role in several AMD-vulnerable cells we will also be able to consider the therapeutic potential of this factor as a possible treatment for AMD.

About the Researcher

Goldis Malek, received her BS and BA degrees in biology and psychology from the University of South Florida and her PhD degree in vision science and physiological optics from the University of Alabama at Birmingham, during which time she developed an interest in studying the pathology and cellular mechanisms underlying retinal diseases. She completed her postdoctoral studies at Duke University in the Department of Ophthalmology. Since 2007, she has been at Duke University where she is currently an Associate Professor, with appointments in the Departments of Ophthalmology and Pathology. She has a strong background in cell biology and a broad understanding of retinal and retinal pigment epithelial cell function in health and disease. This includes the pathology and pathogenic mechanisms involved in dry and wet age-related macular degeneration, an aged disease characterized by accumulation of extracellular debris, cellular degeneration/apoptosis and angiogenesis/neovascularization. Furthermore, she has extensive experience in development of murine models of retinal degeneration.

Dr. Malek’s research focuses on identifying and defining the mechanism of action of nuclear receptors in the aging retina and AMD. To date, her lab has identified several lipid-, steroid hormone-, and toxin-activated nuclear receptors, which may play a role in disease initiation and progression. Her lab utilizes genetic and pharmacological applications and uses in vitro models of retinal pigment epithelial and choroidal endothelial cells, as well as in vivo models. The therapeutic potential of targeting these receptors also is currently under investigation. Presently her labs’ research has been recognized with an Alcon Research Institute Young Investigator Award and a Research to Prevent Blindness award, in addition to BrightFocus funding. Dr. Malek has reviewed grant applications for NEI, serves as a scientific grant review member for several foundations, reviews manuscripts for over 15 journals, and is an editorial board member for Molecular Vision and Current Eye Research.

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