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It's an eye disease where genetics and environmental factors such as ultraviolet light and vigorous eye rub conspire to make the usual curvature of the cornea more sharp, leaving us with double vision and myopic vision.
Stephen Curry, a star of the National Basketball Association, has contributed to the manufacture of a keratoconus, which affects about 1 in 2,000 people, a most visible eye disorder in April.
A $ 2.1 million grant from the National Eye Institute is helping Dr. Yutao Liu, a vision scientist and human geneticist, learn more about the causes of keratoconus and identify areas for better diagnosis, treatment and possibly to prevent progressive disease that usually begins in adolescence.
"We want to help patients better understand what is going on in their vision by better understanding how keratoconus is going and offering physicians better intervention points," says the cell biology department's research scientist. Anatomy of the Medical College of Georgia and James. Jean Culver Vision Discovery Institute, University of Augusta.
Liu developed the first model of keratoconus in mice, which allows his research team to track the evolution of the disease in real time. He further explores the role of mutations in the PPIP5K2 gene, which he found in patients and used to make the new mouse model. It also examines the corneal tissue of people with and without the disease, looking for genes and additional responses.
Keratoconus can start in one eye, then progress in both, although it tends to be more serious in one eye, says Liu. The natural curvature of the clear cornea that easily lets most of the light into our eye becomes thinner, weaker, and more conical. The light, which our eyes and brain convert into images, is refracted, resulting in double vision, astigmatism and severe myopia.
Some confuse vision changes with more common eye problems, but the pace of change is usually much faster with keratoconus, says Liu.
In two multigenerational families with multiple members with the disease, researchers identified two mutations specific to PPIP5K2, a highly expressed gene in human corneas and mice.
Now they want to know more about how mutations cause disease. They think that at least one of the changes made to vision by altered genes is related to the production of ATP, a cellular fuel, in the cornea.
It is known that the function and form of the mitochondria, the cells conducive to the transformation of the food we eat is transformed into ATP, are different in the corneas of patients with the disease. "Patients have found a reduction in ATP production in patients," said Liu, who is again interested in power plants and ATP in his mouse model and his tissue human. The obvious impact of these lower fuel levels is unclear, as if it left the corneal cells weaker or less able to maintain their shape. So that's one of the many questions that Liu wants to answer. Investigators also want to know if, as they suspect, modified mitochondria produce more oxidative stress, already badociated with keratoconus.
They hypothesize that gene mutations as well as environmental factors ultimately alter cellular processes, resulting in thinning of the usually clear and well organized stroma of the cornea through which light must pbad. There also appears to be an apparent change in the outermost epithelial layer of the cornea, which normally helps to nourish the cornea and protect it from invaders such as microbes or even some debris. As the stromal layer thins, the epithelial layer thickens, an apparently harmless but possibly compensatory movement, says Liu.
They use a complete exome sequencing, which examines the protein-coding regions of all our genes, to examine PPIP5K2 mutations in more patients and look for other genes and mutations. new genes.
They search in the two corneal tissues taken for a corneal transplant in patients – which is essentially the only current means of completely correcting the disease – and compare what they find to healthy human corneal tissue.
In the mouse model that they have developed and which, like some families, have undergone mutations of the PPIP5K2 gene, they look downstream of these mutations to see how physical changes that affect vision actually occur.
After three months, mice – who live for about two years and have an accelerated route to most man-like diseases – have a more opaque cornea than clear ones. With collaborators from Duke University, Liu has helped develop software allowing them to use human optical coherence tomography, which uses light to visualize the anatomy of the body. 39, eye, to see this and other changes in the structure of the eye of the mouse, comparatively meticulous. With this mouse version of OCT, they discover in the mouse model that the corneal curvature is rough and that the epithelial layer thickens, like what happens in humans. Within tight deadlines of a mouse, they can even observe the course of the disease and see what happens to mitochondria and ATP.
Our technology can be used to track these changes in real time, "
Dr. Yutao Liu, Visionary Scientist and Human Geneticist
Liu suspects that PPIP5K2 as well as other genes badociated with keratoconus may have similar pathways of action because their results are similar, says Liu. By going through these lines of action, investigators can identify possible points where they could intervene to stop or even possibly prevent the disease in people with genetic mutations that put them at risk, he said.
The progression of the disease tends to stabilize once patients reach their forties, potentially because hormone levels that skyrocket in young people and that are thought to be a contributing factor are beginning to to fall, said Liu. Although the absolute causes are not yet known, the National Keratoconus Foundation states that hormones, as well as genetics and the environment, all seem to play a role. Environmental factors include exposure to ultraviolet light, vigorous eye rubbing, and allergies that can cause vigorous eye rubbing. Other badociations include oxidative stress, a normal result of our regular use of oxygen, which can be destructive at higher levels. The onset of hormones around puberty is also an unproven hypothesis, which brings us back to the fact that most cases are diagnosed at puberty and that they often progress during pregnancy, based on the fundamentals. A percentage of patients operated on by LASIX also develop secondary keratoconus.
According to the National Library of Medicine of the United States, more than a dozen genes are currently badociated with the disease, some of which are involved in the development of the eyes and cornea and in the extracellular matrix between cells.
PPIP5K2, which codes for proteins, is already badociated with autism, autism spectrum disorders, hearing loss and cancer.
Treatments for keratoconus include a variety of contact lenses that can, much like a body shaper, help the cornea to maintain its shape for at least a moment. There is also a cross-linking therapy that can strengthen the cornea and help stop the progression of the disease, but takes about six months to function. A corneal transplant is probably the closest thing to solving the disease, says Liu.
Keratoconus also affects men and women, about 1 in 500 to 2,000 people in total and 5 to 15% of people born with Down syndrome.
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Source:
Georgia Medical College at Augusta University
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