Current Projects

Photoreceptors Degeneration

Photoreceptors are specialized neurons found in the retina that convert light into signals. Rods, which contribute to 95% of photoreceptors, are responsible for night-time vision, whereas cones contribute to the rest of photoreceptors that are responsible for color recognition, high resolution, and central vision. Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, caused by >71 mutations that primarily cause rod photoreceptor death. Cone death always follows rod death and starts after the end of the major rod death phase regardless of the underlying rod specific gene mutations. Accumulating evidence has shown that cone death in RP is due to glucose starvation. However, studying the biology of cone cells in the rod-dominant mammalian retina is particularly challenging. Our overall objective is to define how cones and retinal pigment epithelium are metabolically coupled and to test potential therapies for RP that are designed to restore this relationship. Dr. Wang is collaborating with Dr. Stephen Tsang using unique Cre drivers and conditional overexpression knock-in mouse models to reprogram cone and RPE metabolism.

RGCs Degeneration

Retinal ganglion cells (RGCs) are a type of nerve cell in the eye. Their function is to transmit visual information from the eye to the brain. RGCs have a unique cell shape because they extend very long, thin processes into the brain. This makes RGCs exquisitely vulnerable to problems with the cellular powerhouses, called mitochondria, that produce the energy needed for the RGCs to function. Accumulating evidence links mitochondrial dysfunction to RGC death in diseases like glaucoma and suggests that mitochondrial dysfunction may cause decreased energy production and increased generation of damaging chemicals, leading to mitochondrial and cellular damage, and RGC death. We have generated two knock-in mouse models based on patient mutations. Both genes are located in the nucleus, and their protein products play important roles in mitochondrial function. Our goal is to dissect the molecular mechanisms required to maintain mitochondrial function, particularly within the setting of diseases that cause RGC death, as these discoveries will facilitate development of potential therapies designed to restore mitochondrial function.

Different susceptibility to mitochondrial dysfunction between photoreceptors and RGCs

Although photoreceptors and RGCs are both highly energy-dependent, RGCs are particularly vulnerable during mitochondrial dysfunction even though photoreceptors have a higher density of mitochondria. By comparing three different primary mitochondrial optic nerve disorders, we found RGCs are, in general, affected by mitochondrial dysfunction, whereas variable photoreceptor dysfunction exists in patients with LHON and OPA1, especially with respect to the cone responses. Involvement of photoreceptors are particularly evident in OPA13 after RGC degeneration. Differences in cellular metabolism, oxidative stress, and cell structure may cause various levels of susceptibility in mitochondrial dysfunction. We have successfully generated patient specific knock-in mice using gene-targeting. This novel mouse model will be a good tool to elucidate the underlying mechanism of different susceptibility of photoreceptors and RGCs to mitochondria dysfunction.

Inherited Retinal Dystrophies (IRD)

Before moving to the US, Dr. Wang led a team with the aim of diagnosing IRD. Now, he is collaborating with doctors in Taiwan on this project. They have characterized clinical features and identified novel variants in Taiwanese patients with Inherited Retinal Dystrophies (IRD).