New chemical compound protects against blindness and diabetes in animals -
In a new study by UC San Francisco (UCSF) scientists, a chemical compound designed to precisely target part of a crucial cellular quality control network provided significant protection in rats and mice against the degenerative forms of blindness and diabetes.
in addition to opening a path of development of promising drugs for the wide range of diseases caused by cell loss, new research offers a new vision of how the unfolded protein response (UPR) a network "life or death" cell signaling: When cells are under stress, the UPR ensures that they produce proteins properly configured, but these cells not to this task quickly motivated by the UPR to self-destruction.
A UPR component known as the IRE1 track was generally thought to manage the protection aspects of this response, promoting cell survival by providing cells with biological resources they need to cope with stress, while an additional track, called PERK, has been associated with cell death.
But in the new research, published in July 10, 2014 edition of cell , when the researchers used KIRA6, a small kinase inhibitor molecule they designed to inhibit the actions of IRE1 alpha -the molecular sensor that triggers the way they IRE1 blocked cell death and the conserved function in two experimental models of human diseases.
in two models of retinitis pigmentosa rats, a disease in which the light sensing cells in the eye gradually die off, causing blindness, KIRA6 retained both the number of these cells and visual function. And in mice a known strain as the Akita, which carry a genetic mutation that causes diabetes in early life that the insulin producing beta cells stressed to the degeneracy of the pancreas, KIRA6 protected beta cells of cell death, leading to a two-fold increase insulin production and improved glycemic control.
"This is a huge step forward in our field," said co-senior author Scott A. Oakes, MD, Associate Professor of Pathology at UCSF. "On the surface these seem to be two diseases very different, but the cell death induced by IRE1-is at the root of both. "
the results are the culmination of a" gigantic project, "first establish that the pathway could lead a IRE1 degenerative disease, and to develop and test compounds to address the damage, said Feroz Papa UCSF, MD, PhD, associate professor of medicine and co-lead author and a member of the California Institute for quantitative Biosciences. "It took four years, more than a hundred separate experiments in various contexts, not including replications-and involved 24 researchers in seven laboratories laboratories in four cities."
KIRA6 is the latest a series of compounds (the acronym stands for "Kinase Inhibitors RNase-attenuators) that were originally designed and synthesized in the study co-authors laboratories Dustin J. Maly, PhD, associate professor of chemistry at the University of Washington, Seattle, and Bradley J. Backes, PhD, associate professor of medicine at UCSF.
"Although KIRA6 has shown efficacy in animals," said Papa, "it is important to emphasize that most optimization through medicinal chemistry effort is needed to develop this class of compounds the stage where they could be tested for efficacy in humans through clinical trials. "
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