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Research
The major focus of the lab is retinitis pigmentosa, a group of hereditary retinal degenerations caused by mutations in more than 60 genes. These mutations specifically induce rod photoreceptor degeneration. Patients with retinitis pigmentosa typically experience nyctalopia (night blindness) due to rod dysfunction and degeneration. As the disease progresses, cone photoreceptors undergo degeneration following rod degeneration (secondary cone degeneration). Progressive rod and secondary cone degenerations lead to annual loss of the remaining visual-field area at an experiential rate of about 2.6–13.5%, and tunnel vision and eventually total blindness.
Rod photoreceptors are a marvel of evolution. They are created to detect light with extraordinarily sensitivity. In fact, a human retina is capable of detecting a single photon. On the other hand, rod photoreceptors are vulnerable to degenerative pressure from gene mutations. It is interesting that in retinitis pigmentosa, different gene mutations lead to a similar phenotype outcome of rod degeneration.
In retinitis pigmentosa, we are facing two major questions: why rod photoreceptors are vulnerable to so many mutations, and how to develop treatments for a group disease with such a considerable genetic heterogeneity?
To understand why rod photoreceptors degenerate caused by a particular gene mutation, we study the molecular and morphological features of specific animal models that carry given mutations. More importantly, we want to develop therapies for retinitis pigmentosa. The tremendous genetic heterogeneity makes it difficult to develop mutation-dependent gene augmentation therapies for a specific mutation. We focus our work on mutation-independent therapies. One approach is to protect rod photoreceptors by neuroprotective therapies.
In addition to rod photoreceptors, we investigate retinal ganglion cell degeneration Retinal ganglion cells are retinal output neurons that process and convey visual information from the retina to the visual cortex. Clinical conditions that affect retinal ganglion cell functions can lead to blindness, including glaucoma, ischemic optic neuropathies, hereditary optic neuropathies, and demyelinating disease. Glaucoma is a leading cause of irreversible vision loss. A promising therapeutic strategy for glaucoma is to protect retinal ganglion cells with neuroprotective therapies.
Neuroprotection is to protect the function and survival of neurons with neuroprotective agents. We have a variety of neuroprotective agents, including neurotrophic factors and synthetic small molecule compounds. A typical neurotrophic factor we have been working on is CNTF (ciliary neurotrophic factor). We showed that CNTF protects rod as well as cone photoreceptors. It also promotes regeneration of outer segments in degenerative cones.
Recently, we turned our attention to a protein known as the sigma 2 receptor. The biological function of the sigma 2 receptor was not well understood, but its wide distribution in the body, including in the retinal ganglion cells and photoreceptors. By using a knockout mouse lack of sigma 2 receptors and ischemia-induced retinal ganglion cell degeneration, we demonstrate that the sigma 2 receptor is involved in retinal ganglion cell degeneration and its presence facilitates the degeneration process. In addition, intravitreal injection of a selective high-affinity sigma 2 receptor ligand protects retinal ganglion cell degeneration. We are currently studying many other neuroprotective agents, including their efficacies and delivery routes.
We are developing a novel mutation-independent therapies for both autosomal dominant and recessive retinitis pigmentosa.
Another focus of the lab is to understand how the retina responds to an increase in intraocular pressure. Increase in intraocular pressure is induced by laser photocoagulation of the trabecular meshwork. The retinal morphology is monitored overtime with a custom-made OCT (optical coherence tomography). The retina shows a dynamic change in its morphology in response to an increase in intraocular pressure. We are investigating the underlying molecular and cellular mechanism.
We hope our research will give us a better understanding of the retinal cell biology and retinal degeneration pathology. Importantly, our research could lead to clinical therapies for photoreceptor and ganglion cell neuroprotection.