Glaucoma is a diverse group of blinding diseases whose unifying characteristic is that that they kill the output neuron of the retina, the retinal ganglion cells (RGCs). The Flaum Eye Institute has a large effort aimed at developing new ideas about how glaucoma can be diagnosed and treated. The research being conducted at the Flaum Eye Institute is aimed at understanding the genetics and cell biology that underlie this complex disease. Furthermore, efforts are also underway to develop novel imaging technologies that will be both a powerful research and clinical tools for diagnosing and tracking glaucoma.
Genomic Control of Retinal Ganglion Cell Survival
RGCs appear to be insulted long before vision is lost in glaucoma. These early insult(s) affect the RGCs on a genomic scale—the transcription of hundreds or even thousands of genes are changed. The differences in gene expression in glaucomatous RGCs greatly changes the physiology of the cell. These changes determine the probability that a RGC will survive the glaucomatous insult. Thus, understanding how the transcriptome is controlled during ocular hypertension will lead to a clear understanding of the changes in RGCs that lead to glaucomatous neurodegeneration. Transcription factors (TFs) are proteins that bind to DNA and control gene expression of numerous genes. It is the cumulative effect of a relatively small number of TFs that controls the transcriptome of a cell and it is the transcriptome that controls a cells physiology. Dr. Lin Gan has shown that in RGCs, specific TFs are known to be responsible for cell fate commitment, differentiation and survival during development. Recently, the importance of TFs in maintaining cell viability in adults has become the focus of intense research, including in studies focusing on neurodegenerative diseases. Dr. Gan’s studies are focusing on identifying the gene networks these TFs control in glaucomatous eyes so that we can better understand the disease process and identify molecules that can be manipulated for therapeutic value.
Understanding the Molecular Mechanisms of Anterior Segment Dysgenesis and Pediatric Glaucoma
Anterior segment dysgenesis (ASD) refers to a broad spectrum of clinically-defined eye diseases affecting the anterior segment of the eye. Infants and children that have ASD show iris hyoplasia, irregular and misplaced pupils, hazy corneas, and attachments of the iris to the cornea. In addition, since the anterior segment includes the drainage and fluid secretion structures of the eye, ASD is often associated with an early and severe form of glaucoma. These defects can cause vision loss, as well as have severe cosmetic and associated psychological consequences for the child. The molecular patterning of the anterior segment of the eye is not well understood. The lack of understanding of the development of the anterior segment may be due to the fact that anterior segment development involves complex inductive interactions between tissues derived from diverse sources, including neural tube, neural crest, and surface ectoderm. Dr. Amy Kiernan is defining the molecular signaling pathway that control anterior segment development and pathogenesis. The goal of her laboratory is to understand the molecular genetic patterning of the anterior segment of the eye, so that we can better understand, diagnose, and eventually treat children suffering from ASD.
Molecular Mechanisms of Vision Loss in Glaucoma
Ultimately, vision loss in glaucoma is caused by the death of the output neurons of the retina, the retinal ganglion cells. Unfortunately, no molecules are known to be necessary for RGC death in glaucoma patients. Dr. Richard Libby is using a variety of genetic resources and cell biological techniques to identify the molecules and genes that are activated in sick RGCs. Ultimately, Dr. Libby aims to characterize the entirety of the molecular pathways that are controlling whether RGCs live or die in glaucoma. He aims to provide an integrated understanding of RGC death in glaucoma that will enable us to identify key targets for therapeutic development. Furthermore, Dr. Libby’s experiments will contribute to building a genetic frame work for RGC death in glaucoma, eventually leading to genetic tests that could predict a patients susceptibility for developing glaucoma. Understanding the molecular mechanisms that are activated in RGCs during a glaucomatous insult is critical to developing therapies aimed at preventing vision loss in glaucoma patients.
Non-Invasive Imaging of Glaucomatous Retinas
FEI's Dr. William Merigan uses adaptive optics laser scanning ophthalmoscopy, developed by the Center for Visual Science's Dr. David Williams, to image in vivo the retinas of macaque monkeys and humans in the study of glaucoma. This approach allows imaging of the retinal vasculature and retinal neurons with unprecedented precision in both normal and diseased states. The Flaum Eye Institute also images the vasculature of the nerve fiber layer, the radial peripapillary capillaries (RPCs) using fluorescein contrast, marking the first time that this vasculature can be examined in vivo. In addition, Drs. Merigan and Williams are leading an effort to image retinal ganglion cells, which degenerate in glaucoma. Although these cells are transparent, making optical imaging difficult, developing a method to see them could provide a quantum leap forward in the diagnosis and treatment of glaucoma.