New Approach for Regenerating the Injured Optic Nerve

Ephraim F. Trakhtenberg, PhD
University of Connecticut Health Center (Farmington, CT)
Year Awarded:
2017
Grant Duration:
July 1, 2017 to June 30, 2019
Disease:
Glaucoma
Award Amount:
$150,000
Grant Reference ID:
G2017204
Award Type:
Standard
Award Region:
US Northeastern
Ephraim F. Trakhtenberg, PhD

The Molecular Mechanisms of RGC Axon Growth and Regeneration

Summary

The biological molecular mechanisms controlling the growth of connections in the central nervous system (CNS) are still poorly understood. The inability of the eye to regenerate such connections to the brain is the key reason why vision is lost from optic nerve damage, which can happen in a disease such as glaucoma, cannot be restored. We propose to identify novel biological regulators of the intrinsic ability of the retinal cells to regrow such connections between the eye and the brain. These studies could lead to the development of therapeutics for restoring simple visual abilities to those who became blind due to angle-closure glaucoma, and possibly other types of glaucoma.

Details

Currently, no treatment exists for clinical use that could induce regeneration of retinal ganglion cell (RGC) axons for restoring vision loss due to optic neuropathy caused by angle-closure glaucoma. Favorable results from the completion of the proposed project are expected to provide much-needed pre-clinical proof-of-concept data for translation to clinical trials evaluating treatments for the acute phase of angle-closure glaucoma. Such therapeutics would be particularly promising if administered in conjunction with trophic factors to support the health of injured RGCs.

Our approach is innovative in that we propose to study a novel group of bioinformatically-predicted factors, which we hypothesize cooperate in controlling RGC axon growth and regeneration. We will leverage state-of-the-art bioinformatic and biological approaches for investigating how these factors interact in combination to regulate axon growth during RGC development and test the potential of such factors for regenerating RGC axons in a rodent model of optic nerve injury.

The scientific knowledge gained from this research could be paradigm-shifting for understanding the regulation of axon growth and regeneration in the CNS. Furthermore, the success of this project can lead to the development of novel axon-regenerating therapeutics that could transform the clinical treatment of angle-closure glaucoma and other types of optic neuropathies, as well as have the potential to be adapted to regenerating the long-distance axonal projections damaged by spinal cord injury, brain trauma, and white matter stroke.

About the Researcher

Dr. Ephraim Trakhtenberg is an assistant professor of neuroscience at the University of Connecticut Medical School, where he leads the Neuroregeneration Laboratory. Dr. Trakhtenberg received an MS degree in biological sciences from Stanford University and a PhD in neuroscience from the University Of Miami Miller School Of Medicine. He did a postdoctoral fellowship in neuroscience at Harvard Medical School, Boston Children’s Hospital. During his doctoral and post-doctoral work under the mentorship of Jeffrey Goldberg, MD, PhD, and Larry Benowitz, PhD, Dr. Trakhtenberg discovered (1) how Set-β and PP2A proteins regulate axon growth; (2) the role of serotonin receptor 2C in neurite growth and processing of visual information; and (3) that inhibiting the transcription factor Klf9 acts synergistically with zinc chelation in stimulating axon regeneration. In addition, in collaboration with the Harvard Medical School bioinformatics team, he discovered (4) how global parameters of the transcriptome differ between various cell types. These discoveries have been published in the Journal of Neuroscience, Journal of Biological Chemistry, Developmental Neurobiology, and Scientific Reports. Dr. Trakhtenberg is a reviewer for a number of international journals such as Neuropharmacology, PLOS One, and Scientific Reports. His research accomplishments have been recognized through fellowship awards, junior investigators awards, and other awards. The current focus of Dr. Trakhtenberg’s research is on solving the fundamental problem of the failure of CNS projection neurons to regenerate injured axons and developing translational approaches for treating optic neuropathies (eg, glaucoma) and other types of CNS injuries.

Personal Story

The mind and the brain captivated me from a young age and led to me exploring the theological and philosophical models of the mind during my BA studies. Next, I earned a PhD in psychology to gain insight into the inner workings of the brain, followed by an MS in biological sciences to develop a deeper understanding of the molecular basis of behavior and brain functions. While studying biological sciences at Stanford I interacted with amazing scientists, such as Luis de Lecea, PhD, in whose laboratory I received my first hands-on experience in molecular neuroscience, and Robert Sapolsky, PhD, who was my advisor. The program environment and discussions with leading scientists enabled me to explore various areas of neuroscience, which were all fascinating. However, one topic, the potential for neuroregeneration in the brain, resonated particularly strongly with me. It was seconded by my desire to understand the nature of consciousness, although with current technologies this topic may remain beyond our understanding. Consistent with my inspiration to advance the field of neuroregeneration, I have pursued PhD and postdoctoral training in neuroscience, with the focus on neuroregeneration. After completing my training under the mentorship of Jeffrey L. Goldberg, MD, PhD and Larry I. Benowitz, PhD, in 2016 I joined the Department of Neuroscience at the University of Connecticut Medical School, as a tenure-track assistant professor, where I have established and lead the Neuroregeneration Research Laboratory. The focus of my laboratory is on exploring novel approaches for solving the fundamental problem of the failure of CNS projection neurons to regenerate injured axons and developing translational approaches for treating optic neuropathies (e.g., glaucoma) and other types of CNS injuries. Funding from the BrightFocus Foundation and its donors will foster scientific discovery, which will provide a new hope to those who became blind due to glaucoma to see again, as well as to those who suffered brain and spinal cord trauma or stroke to recover some of the lost functions.

Publications

Kim J, Sajid MS, Trakhtenberg EF. The extent of extra-axonal tissue damage determines the levels of CSPG upregulation and the success of experimental axon regeneration in the CNS. Sci Rep. 2018 Jun 29;8(1):9839. doi: 10.1038/s41598-018-28209-z. PubMed PMID: 29959434; PubMed Central PMCID: PMC6026156. PubMed Icon Google Scholar Icon

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