Studying Gene Regulation Networks in RGCs for Novel Neuroprotective Targets

Yang Hu, MD, PhD
Stanford University (Stanford, CA)
Year Awarded:
2018
Grant Duration:
July 1, 2018 to June 30, 2020
Disease:
Glaucoma
Award Amount:
$150,000
Grant Reference ID:
G2018183
Award Type:
Standard
Award Region:
US Northwestern

Identify the Effectors and Regulators of Endoplasmic Reticulum Stress that Govern Glaucomatous Degeneration

Summary

Glaucoma is the most common cause of irreversible blindness and by 2040 will affect more than 100 million people between 40 and 80 years of age, worldwide. Glaucoma is characterized by optic nerve neuropathy with retinal ganglion cell (RGC) axon degeneration followed by progressive RGC death. Understanding gene regulation mechanisms that are associated with RGCs at normal function, under disease, or after treatment, is essential for identifying novel therapeutic targets and innovative and efficient neural repair strategies. We are taking advantage of newly developed genetic tools to elucidate the comprehensive gene regulatory networks that will serve as a blueprint for developing novel and effective neuroprotectants for glaucoma.   

Details

Glaucoma is characterized by optic nerve neuropathy with retinal ganglion cell (RGC) axon degeneration followed by progressive RGC death. Our long-term goal is to develop safe and effective neuroprotective agents for glaucoma patients, through our efforts to elucidate the molecular mechanisms of glaucomatous degeneration. Our previous studies identify a detrimental effect of a specific stress response on RGC survival. However, how this stress response contributes to neurodegeneration is unclear. We reasoned that identifying specific downstream effectors and upstream regulators of this specific stress condition is essential for efficient neural repair.  We are taking advantage of newly developed genetic tools to survey gene expression and epigenetic regulatory elements that are associated with RGC at normal function, under disease, or after treatment. Through this effort, we will be able to draw a comprehensive gene regulatory network in RGC specifically, which then serve as a blueprint for developing novel and effective neuroprotectants for glaucoma.   

About the Researcher

I have a strong longstanding interest in neurodegeneration and axon regeneration, especially in retina and optic nerve tissue. My lab focuses on understanding the mechanisms responsible for neuronal degeneration and axon regeneration after injury or diseases, with the goal of building on this understanding to develop effective strategies to promote neuroprotection and functional recovery. We were the first to discover that optic nerve injury induces endoplasmic reticulum (ER) stress and activates the classical unfolded protein response (UPR) pathways. We subsequently demonstrated that manipulation of UPR pathways in different ways synergistically increases survival of RGCs, delays optic nerve degeneration and preserves vision after optic nerve traumatic injury or glaucoma. Based on these findings we propose that neuronal ER stress is the common mechanism for neurodegeneration. Consistently, we detected ER stress in RGCs in experimental autoimmune encephalomyelitis (EAE a rodent form of multiple sclerosis) and optic neuritis models, and modulation of ER stress also has similar protective effects on RGCs and the optic nerve. We also pioneered in elucidating the neuronal intrinsic control of optic nerve regeneration. We demonstrated that AKT (protein kinase B), interacts with mTORC1 and mTORC2 and their downstream effectors S6K1, 4E-BP and GSK3β to coordinate optic nerve regeneration. We actively work on developing novel adeno-associated virus (AAV) vectors and RGC specific promoters/enhancers for AAV-mediated gene therapy to promote neuroprotection, axon regeneration and functional preservation of vision in optic neuropathies.

Personal Story

I was initially trained as a clinical ophthalmologist, providing me with a deep understanding of eye diseases and a mastery of surgical techniques. Later due to an interest in basic research, I entered a PhD program at Cornell, where I studied signal transduction in the immune system with Dr. Lionel Ivashkiv. I switched back to neuroscience research in my postdoctoral training at Harvard, with Dr. Zhigang He, focused on central nervous system axon regeneration. I spent 1.5 years at Merck afterwards, and become familiar with the process for developing drugs for neurodegenerative diseases and increasing my understanding of translational research. I switched back to academia from industry, as I prefer the freedom of pursuing the science of most interest to me. I got my first grant support from BrightFocus years ago, which played a critical role in initiating my academic career pathway. I am extremely grateful to the donors of the BrightFocus Foundation for funding my continuing efforts on glaucoma neuroprotection research that is built upon the previously funded project.

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