F.M. Kirby Center for Molecular Ophthalmology
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Kenneth Shindler's Lab

Research

Principal Investigator:

 

Kenneth S. Shindler, M.D., Ph.D.
Assistant Professor of Ophthalmology

shindler photo Dec 2010.jpg

Education:

Brown University: B.S. (Biochemistry) 1991.
Washington University: MD, PhD (Neuroscience) 1999.

Research Interests:

  • Mechanisms of neuronal damage in optic neuritis and multiple sclerosis
  • Evaluation of neuroprotective therapies for retinal ganglion cells

Description of Research:

The Shindler laboratory is studying animal models of optic nerve injury, with a focus on optic neuritis, an inflammatory disease of the optic nerve that often occurs as part of the central nervous system inflammatory neurodegenerative disease multiple sclerosis (MS).  Episodes of inflammation can lead to permanent damage and loss of nerve cells, resulting in decreased vision and other neurological dysfunction in MS patients.  Studies in the lab aim to expand our understanding of the mechanisms of nerve cell damage in this disease, and potential new therapies are being evaluated to prevent nerve damage and preserve vision.

In the animal model EAE, mice immunized with specific myelin antigens, develop inflammation, loss of myelin, and nerve damage in the brain, spinal cord, and optic nerves, similar to MS patients.  Over two thirds of eyes in EAE mice develop optic neuritis, and significant numbers of retinal ganglion cells die following an acute attack of optic neuritis. While EAE provides an important autoimmune disease model of optic neuritis, the underlying cause for optic neuritis in patients is not known, and some evidence suggests that optic neuritis can be induced in part by inflammation following viral infection.  We therefore have also characterized optic neuritis in a viral-induced animal model of multiple sclerosis triggered by infection with mouse hepatitis virus.

One class of compounds that has shown excellent promise as a potential neuroprotective therapy in these optic neuritis models is activators of SIRT1, a deacetylase involved in cell stress responses and cell survival.  Treatment of EAE mice with several different SIRT1 activators significantly attenuates the loss of retinal ganglion cells in eyes with optic neuritis.  SIRT1 activators also reduce damage to spinal cord neurons and promote improved neurological recovery from EAE.  These novel therapies have tremendous potential for preventing neurodegeneration in optic neuritis and MS patients, and may have the ability to prevent damage to retinal ganglion cells and other neuroretinal cells in a variety of eye diseases.  Ongoing studies are examining the molecular mechanisms by which SIRT1 activators prevent neuronal damage.  Using the optic neuritis models characterized in the lab, other potential neuroprotective therapies will also be tested for their ability to prevent retinal ganglion cell death.

 

University of Pennsylvania | Perelman School of Medicine