SCIENCE

The long-term goal of our work is to use stem cell biology, genetics, and epigenetics as languages to decipher the pathogenesis of blinding retinal diseases and eye/orbit cancers. Ultimately, we hope to use the foundational insights to better diagnose and treat these diseases, most of which lack molecularly targeted therapies that restore vision or treat the cancer.

To understand the role of epigenetic mechanisms in retinal development and disease, we employ conditional knockout mice, and wild-type and mutant embryonic stem cell-derived 3D retinal organoids with alterations in specific chromatin modifying enzymes. We also dissect the genetic and epigenetic mechanisms underlying cancers that occur in the eye and orbit.

The explosion of gene editing innovations like CRISPR/Cas9, next-gen sequencing based epigenetic tools like ATAC-seq, and small-molecule chromatin modifiers in drug development for cancer and inflammatory disorders offer us a new toolbox to integrate mechanistic studies with translational advances. With insights gleaned from these studies, we can assess whether some of the agents that target critical epigenetic pathways in retinal and tumor cells can be exploited for use in blinding retinal disorders and eye/orbit cancers.

We achieve our goals through integration of:

Discovery

  • Uncovering 3D organoid and mouse-based phenotypes linked to genetic dysregulation of epigenetic genes.
  • Detailing the genome-wide changes in chromatin that accompany major cell fate decisions and tumorigenesis.
  • Defining the landscape of the actionable cancer genome in eye/orbit cancers.

Mechanism

  • Loss- and gain-of-function studies that illuminate underlying mechanisms linked to genome-wide, chromatin changes during ocular development and tumorigenesis.
    • Integration of CRISPR/Cas9-driven gene editing with ChIP-seq, RNA-seq, ATAC-seq and single cell sequencing technologies.

Disease

  • Modeling blinding diseases and eye cancers linked to epigenetic perturbations through mouse models and stem cell-derived 3D retinal organoids.

To achieve these objectives, we collaborate with researchers and clinicians in a variety of departments and programs, including the Department of Pathology, Taubman Medical Research Institute, and University of Michigan-wide faculty, and beyond, involved in epigenetics and drug discovery. Through these collaborative efforts, our ultimate goal is to develop novel pharmacologic genetic, epigenetic and cell-based clinical diagnostics and therapies to promote regeneration, and reduce scar and tumor formation in patients with blinding retinal diseases and eye cancers.

Finally, the Rao Lab explores a variety of clinical retina and eye cancer themes, from patient phenotyping and case reports, case series, to clinical trials related to natural history of disease, vitreoretinal surgery, and wide-field retinal imaging.