I. Genetics and Cell Biology of Retinal Degeneration

We study the molecular basis of retinitis pigmentosa (RP). RP is a progressive retinal degenerative disease, affecting ~1 in 4,000 people. The genetic causes responsible for retinal degenerative diseases are extremely heterogeneous and, at present, there is no effective therapy for RP. Our earlier work has identified mutations in the rhodopsin gene in patients with autosomal dominant RP. We dissected the biochemical and cellular defects of various RP mutant rhodopsin proteins, because a thorough understanding of a molecular defect can lead to effective treatments.

The visual cell is highly polarized and compartmentalized in both morphology and function. No in vitro photoreceptor cell model is currently available. We have developed a cost-effective, highly efficient method for in vivo photoreceptor gene targeting. We use this method to characterize the heterogeneity of RP in vivo. The insights derived from this method may eventually be useful for designing sight-preserving therapies for RP.

Our previous work showed that defects in vectorial trafficking of rhodopsin may be the root cause of photoreceptor cell death in some types of RP. Thus, we study how rhodopsin is translocated from its site of synthesis to where it functions, and how the transport is controlled and regulated. Finally, we ask how the impairment of rhodopsin transport leads to photoreceptor death. These topics are a central interest in cell biology and neuroscience. They are also highly relevant for our understanding of the etiology of various degenerative retinal diseases.


II. Vectorial Protein Transport and Cell Polarity Establishment

We study the role of cytoplasmic dynein and its regulation in basal-to-apical transport in polarized epithelial cells. We investigate the mechanisms determining and regulating the cargo-motor recognition and how cells utilize dynein to accomplish various cellular activities.

III. Unconventional Roles of Dynein Light Chains in Axonal Outgrowth and Neurogenesis

Increasing evidence suggests that several dynein light chains, such as Tctex-1, can act outside the dynein motor complex. For example, our recent studies show that the Tctex-1 plays a key role in multiple steps of hippocampal neuron development, including initial neurite sprouting, axon specification, and later dendritic elaboration. Tctex-1 carries out these activities through its ability to modulate actin dynamics and Rac1 activity. Current investigations are aimed at discovering signals and regulators for Tctex-1's function in growth cone motility.

Our recent studies showed that Tctex-1 is highly abundant in neural progenitors at the germinal zones of adult brains, indicating its importance in neurogenesis. We are currently investigating the putative roles of Tctex-1 in the cell-fate determination of neural progenitors.



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