BLOOMINGTON, Ind.—In a move targeted toward potentially discovering new methods for developing more effective drugs or new drug targets to prevent blindness, the National Institutes of Health’s (NIH) National Eye Institute has presented a five-year, $1.9-million grant to Indiana University (IU) to advance basic research on blindness caused by genetic disorders and aging.
The grant, which will run until July 2021, was awarded to Andrew Zelhof, an associate professor in the IU Bloomington College of Arts and Sciences’ Department of Biology. Zelhof plans to investigate the effect of both congenital birth defects and age on the eye using insects as a model species.
“The basic genetic insights from these experiments will address issues common to all photoreceptors across taxa, from flies to humans,” Zelhof said in a press release. “Understanding the functional blueprints for designing ways to see—and the genes required for these designs—will have a direct impact on our basic knowledge regarding the comparative biology of visual systems.”
The focus of the early-stage research supported under the NIH grant will be on studying cellular and molecular mechanisms in the eyes of Drosophila melanogaster, a species of fruit fly, Zelhof says, adding that research on Drosophila can provide important new insights into human eyes due to the highly conserved nature of these mechanisms in flies and humans, which possess approximately 70 percent of the same genes.
Zelhof’s previous research, for example, has shown that the protein known as prominin-1 plays a role in the development of fruit fly photoreceptors, which could lead to applications for the treatment of prominin-induced human retinal degeneration as well as autosomal recessive retinitis pigmentosa, an inherited eye disorder that causes tunnel vision and eventual blindness.
The new research at IU, thanks to the grant, will develop a more robust model of the mechanisms that drive both this retinal degeneration and synaptogenesis, according to Zelhof. Synaptogenesis is transfer of information between the light-sensing photoreceptors to the higher-order neurons of the brain that play a role transforming these light impulses into images.
Zelhof tells DDNews that delineating the conserved fundamental processes of photoreceptor differentiation and the maintenance of neuronal identity will be applicable to and required for developing therapeutic interventions for both retinal and neuronal degenerative diseases.
“To date, the molecular networks required for specifying neuronal cell types, including photoreceptors, have been investigated meticulously—but the molecular and cellular mechanisms that promote and maintain photoreceptor identity remain poorly understood,” Zelhof explains. “Our proposed work utilizes the paradigm of Glass-mediated differentiation. Our recent results demonstrate that Glass choreographs the expression of a network of genes required for all aspects of photoreceptor differentiation. Thus, this research leverages the genetic strengths of Drosophila neuronal development to investigate and reveal mechanisms required for the differential assembly, functional maturity and maintenance of photoreceptor synapses and mechanisms of light induced degeneration.”
The proposed research “will establish foundational knowledge of photoreceptor differentiation that will have widespread impacts on understanding and developing treatments for numerous diseases, from retinal degeneration to epilepsy to neuropathic pain,” notes Zelhof.
The generation of a functional visual system requires the creation of many neuronal cell types, including retinal ganglion, amacrine and photoreceptor cells, he explains. The transcriptional and cell signaling pathways governing the specification of neurons are well characterized and share considerable conservation between rhabdomeric (Drosophila) and ciliary (human) visual systems.
“Nonetheless, we do not understand the mechanisms regulating differentiation and the maintenance of retinal neurons,” Zelhof points out. “Moreover, with respect to visual systems, inherent genetic defects or dysregulation of these later neuronal differentiation events can lead to retinal degeneration. Thus, there is a critical need to understand the molecular processes governing both the morphological and functional differentiation of retinal neurons and the stabilization of their cell fate. In the absence of such basic insights into the mechanisms of differentiation and maintenance of neuronal integrity, effective interventions for retinal degeneration or regenerative therapeutics will continue to be an elusive goal.”