Shiming Chen, PhD

My lab studies the genetic and epigenetic mechanisms regulating photoreceptor gene expression in the retina, and how disease mutations disrupt these mechanisms and strategies to overcome the mutation effects. More specifically, we have focused on the cone-rod homeobox transcription factor CRX, which is essential for development and maintenance of photoreceptor function. Mutations in the human CRX gene have been linked to both recessive and dominant blinding retinopathies with a wide-range of phenotype severity and age of onset. No treatment is currently available. To understand how CRX mutations cause disease, we have divided CRX mutations into four classes and created mouse models carrying representative mutation(s) for each class. We are using these models to understand disease phenotypes and the underlying molecular mechanisms. We are also using in vitro high-throughput sequencing-based assays to determine how different disease mutations alter CRX’s DNA binding specificity and regulatory activity. We perform integrative analyses to determine how mutation-triggered biochemical property changes alter CRX function at genomic target sites, leading to gene misregulation and loss of photoreceptor integrity in model mice. In the meantime, we are developing general treatment strategies, such as tunable gene augmentation, using mouse models of all CRX mutation classes. Finally, we are committed to translate findings from laboratory research to clinical practice. To this end, we have recently initiated a clinical study on phenotype-genotype correlations of CRX retinopathies. Our ultimate goal is to translate treatment strategies developed in animal models to feasible and effective therapies for patients.

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