Low-Oxygen Mediated Proteins Play Pathological Role in Glaucoma

Shahid Husain, PhD
Medical University of South Carolina (Charleston, SC)
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2019
Disease:
Glaucoma
Award Amount:
$150,000
Grant Reference ID:
G2016157
Award Type:
Standard
Award Region:
US Southeastern
Shahid Husain, PhD

Pro-Inflammatory Cytokine Regulation by HIF-1α in Glaucoma

Summary

In glaucoma, neurons are dying slowly and leading to blindness. Numerous detrimental factors, including low oxygen (hypoxia), play key roles in the progression of this disease. Our team has shown that the neurotoxic proteins, including cytokines and hypoxia-inducible transcription factor-1 alpha (HIF-1 alpha) are up-regulated and facilitate neuronal death in glaucoma. The studies in this project seek to limit the up-regulation of such neurotoxic proteins to slow/halt neuronal death in glaucoma.

Details

This project will determine if blocking HIF-1α-stabilization provides retina neuroprotection via suppression of pro-inflammatory cytokines.

In Specific Aim #1, the studies will determine what changes in RGC function and integrity occur when HIF-1alpha activity is manipulated, using an in vivo model. Studies will also determine that how RGCs die during the progression of glaucoma, and if there is involvement of caspases in RGC death. In Specific Aim #2, the studies will determine if HIF-1α blockage by selective HIF-1α inhibitors blocks the production of pro-inflammatory cytokines and provides neuroprotection. The idea that RGC neuroprotection may result from blocking HIF-1α stabilization and subsequently blocking its downstream targets (e.g., pro-inflammatory cytokines) during the early stages of glaucoma is highly innovative and it has not been tested. The outcome of this study will pave the way to identify new therapeutic agents for glaucoma therapy. A comprehensive understanding of HIF-1α and its associated genes will be critical to develop HIF-1α inhibitors for clinical trials. The successful completion of these studies will be translational, as it will directly apply to glaucoma therapy.

About the Researcher

My primary research focus is to develop neuroprotective strategies and agents for the treatment of glaucoma and ischemia/reperfusion-induced retinopathies. An emerging hypothesis suggests that a) an hypoxic component in response to glaucomatous injury plays key role in the degeneration of retinal ganglion cells (RGC), and b) that the blockage of hypoxia-inducible transcription factor-1α (HIF-1α) activity/expression can rescue RGCs. Elevated levels of HIF-1α in human glaucoma and experimental glaucoma models have been shown. However, the molecular mechanisms involved in HIF-1α-induced RGC death are not clearly defined. I have the necessary expertise, leadership, training, and motivation to carry out this research project, including a strong background in ocular pharmacology, physiology, electrophysiology, immunology, signal transduction, and protein biochemistry. I was trained as a protein biochemist during my doctoral work, then completed postdoctoral training in ocular pharmacology studying therapeutic potentials of numerous intraocular pressure-lowering drugs and their impact on aqueous humor dynamics. I have extensive experience in signal transduction work (e.g., cAMP, Ca+2, protein kinases and phosphatases) using ocular and non-ocular tissues. During the last decade, my laboratory has been working to define neurodegeneration mechanisms in glaucoma and ischemia/reperfusion-related retinopathies using a variety of techniques (including immunological techniques) and agents. My laboratory has identified several molecules and ligands that can provide retina neuroprotection against glaucoma and ischemia/reperfusion-induced retinal injuries as determined by various in vitro (e.g., RGCs, ONH astrocytes, microglia cells) and in vivo (Morrison and microbead glaucoma models, and acute ischemia model) approaches.

Personal Story

My father had glaucoma in one of his eyes and I saw how his vision and quality of life declined over time. It is so painful to see that in someone who you love the most and yet cannot do much to help. He passed away in 2002, while I was working at Medical College of Georgia, trying to understand the role of prostaglandins in the intraocular pressure regulation in glaucoma. At that point, I really wanted to get involve more deeply in glaucoma research and to discover novel therapies. In the last 14 years, I have been actively engaged to find new agents and/or pathways that can be a potential target to improve vision quality in glaucoma patients.

It is estimated that over 3 million Americans have glaucoma, and that nearly 70 percent of those patients are age 65 or older. Direct costs to treat glaucoma in the U.S. are estimated to be $2.9 billion annually, and this disease becomes increasingly expensive to evaluate and treat as the population ages. I am very hopeful that one day we will find a cure. Such hopes can become a reality if organizations like BrightFocus Foundation and its supporters continue to support novel and innovative ideas to bring about highly useful therapies for glaucoma.

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