The UW Department of Ophthalmology and Visual Sciences strives not only to help those already suffering from visual impairment, but also to understand the basic causes of eye disease.  By finding out how and why eye disorders develop, UW researchers are seeking enhanced methods to prevent and treat a variety of eye conditions.

In addition to clinical research involving patients, scientists representing the best and brightest in their field are studying the basic mechanisms of disease using molecular and cell biology techniques in the laboratory. With the expertise of these researchers, combined with cutting­edge technology and modern laboratories, it's easy to see why the UW is the nation's second leading center in obtaining grants for visual research.

The following is an update on the current research being performed in the UW eye research laboratories that were funded with the generous support of the Wisconsin Lions.

Studying Suicidal Cells

One area of ground-breaking research focuses on how and why certain cells kill themselves through a process called apoptosis. By better understanding the molecular basis for this process, UW ophthalmology researchers are coming closer to developing new therapies for treating patients with glaucoma, retinoblastoma and retinal ischemia.

"With many diseases, other cells or toxins attack healthy cells and cause them to die," says Robert W. Nickells, PhD, UW assistant professor of ophthalmology and visual sciences and neurophysiology. In apoptosis, the cells receive a signal that causes them to turn themselves off these cells essentially commit suicide. This process is controlled by genes that are turned on in the dying cells.

Sometimes apoptosis is a good thing, such as when tumor cells turn themselves off and die. However, when cells that carry visual information from the retina to the brain die through this process, which happens in glaucoma, it causes irreversible visual impairment or blindness. Nickells is searching for ways to manipulate genes to turn on or turn off the cell death process, which may give new hope to glaucoma patients and children affected by retinoblastoma, a malignant eye tumor.

Neuro-ophthalmologist Leonard A. Levin, MD, PhD, is a UW assistant professor of ophthalmology and visual sciences, neurology and neurological surgery who studies apoptosis in the eye, focusing on the response of retinal cells to ischemia a stroke of the eye and optic nerve injury. By using molecular biology techniques to find which genes are turned on or off when the main blood supply to the retina or optic nerve is interrupted, Levin hopes to pave the way for new therapies.

"Once we understand the mechanisms of death in these cells," says Levin, patients with loss of the retinal or optic nerve blood supply may in the future undergo treatment directed at the molecules of neuronal death, so that the retina may live.

Binding Can Be Blinding

The newest member of the department's team of scientists, Arthur S. Polans, PhD, is also studying diseases of the eye, but one disease he studies doesn't originate in the eye itself. Polans discovered that certain tumors, not eye tumors, produce a protein termed recoverin that triggers an immune response that ultimately leads to visual impairment or blindness. This phenomenon, known as cancer­associated retinopathy (CAR), occurs when a tumor located in the lung or elsewhere in the body produces recoverin, a protein normally found only in photoreceptors, the cells of the retina that receive visual information. An immune response toward recoverin in the tumor ensues, but photoreceptors inadvertantly die, which leads to irreversible vision loss.

Polans, an associate professor of ophthalmology and visual sciences and biomolecular chemistry, found that not all tumors produce recoverin, but those that do typically cause visual impairment, often the first sign of such a tumor. CAR patients can go from 20/20 vision to complete blindness in just a few months or in some cases overnight. Patients are fortunate if their ophthalmologist recognizes the symptoms and the tumor is found in an early, treatable stage.

By studying photoreceptor cells from patients with this rare condition, Polans developed a laboratory test to aid in diagnosis and treatment of this disorder and the associated cancer.

"We've had 100 percent correlation between detecting recoverin antibodies and detecting cancer," says Polans. "Life expectancy for those who go undiagnosed and untreated is about six months; with early detection, people are still alive two years later."

By developing an animal model for CAR, Polans can study basic mechanisms of the disease in rats and is involved in ongoing gene mapping studies to determine how and why the disease occurs and progresses. Polans is using this knowledge to study other diseases as well, including uveal melanoma, the most frequently occurring adult eye tumor.

His research focuses on finding out more about the functions of certain proteins associated with this malignant tumor.

"Our goal is to help doctors manage the disease," says Polans. "Ultimately, we want to know if the function of certain molecules can be specifically blocked so progression of the tumor can be stopped."

Understanding Flies Eyes

Like Polans, Nansi Jo Colley, PhD, also uses an animal model to better understand eye diseases in humans. Colley, an assistant professor of ophthalmology and visual sciences and genetics, uses Drosophila, or common fruit flies, as a model to study hereditary retinal degeneration in humans.

Many genetic researchers, study Drosophila because of its surprising genetic similarity to humans and because they are amenable to genetic manipulation. In addition, a single mating can result in as many as 150 offspring within 10 days, which allows researchers to easily study many generations and a large number of flies in a relatively short period of time. Colley also notes that current studies are able to draw upon information gathered from more than a century of classical genetic analysis involving these organisms.

"All of these factors, combined with modern advances in molecular analysis and gene manipulation, make flies an excellent model system for studying inherited eye diseases in humans," says Colley.

Colley's research focuses on a visual pigment found in both Drosophila and human eyes called rhodopsin. Over twenty-five percent of the cases of an inherited degenerative retinal disorder in humans called autosomal dominant retinitis pigmentosa (ADRP) are linked to mutations in rhodopsin. Colley is now investigating how rhodopsin is made and how biochemical defects in rhodopsin result in retinal degeneration.

"We have isolated and characterized rhodopsin mutants in Drosophila that act dominantly to cause retinal degeneration and four of these correspond to identical mutations identified in human patients with ADRP," says Colley. "We've also demonstrated that the retinal degeneration in flies results from defects in rhodopsin maturation during its synthesis. We think that a similar mechanism may be occurring in humans."

Colley is now looking for novel proteins involved in rhodopsin maturation, targeting and transportation during its biosynthesis. "In essence, we' re looking for zip-code-like proteins that target rhodopsin to its proper location within the cell," she says.

By looking at the molecular/genetic basis of this process, Colley hopes to provide information that physicians can use to find ways of slowing the disease progression, including drug treatments or gene therapy.