In the study, published in the journal Nature Medicine, the researchers report that defective signaling for a protein called the peroxisome proliferator-activated receptor-ã (PPAR-ã) accounts for a portion of disease symptoms in cystic fibrosis, and that correction of the defective pathway reduces symptoms of the disease in mice.
In the paper published in the February 14 edition of the journal, lead investigator Gregory Harmon, MD, study supervisor Christopher Glass, MD, PhD, professor of cellular and molecular medicine, and colleagues show that both mice and cells from patients with cystic fibrosis have a defect in signaling for PPAR-ã, as a result of reduced levels of prostaglandins that activate the receptor.
Cystic fibrosis is the most common, potentially lethal genetic disease among whites, occurring in one in 3,000 births. The disease is a multisystem condition that leads to progressive lung failure, pancreatic failure and gastrointestinal obstruction, or blockage.
"Cystic fibrosis results from a genetic mutation in a channel, or membrane pore, that facilitates the transport of chloride and bicarbonate electrolytes from inside the cell to the spaces outside the cell," said Harmon. "Loss of the cystic fibrosis pore channel results in inflammation and mucus accumulation. It also results in dehydration of the cell surfaces that make up the lining spaces inside the lungs and other affected organs, such as the intestinal tract."
Exactly how the process occurs has been a matter of intense scientific scrutiny; yet despite numerous therapeutic advances, individuals with the disease continue to endure a shortened lifespan. "Someone born in the 1990s with cystic fibrosis is expected to live to an age of around 40," Harmon added.
Working with isolated cells from mice and human cell lines from patients with the disease, Harmon identified that multiple genes affected by PPAR-ã were reduced in cystic fibrosis. When the researchers treated mice with cystic fibrosis with the drug rosiglitazone, a thiazolidinedione drug that binds and activates PPAR-ã, gene expression was largely normalized and survival improved. The drugs also corrected part of the inflammatory process in the tissue. Deleting the PPAR-ã protein in the intestine of mice worsened the disease, leading to mucus accumulation in the intestine. Additionally, the researchers found that activating PPAR-ã could increase bicarbonate production in the intestinal tissue by increasing the activity of bicarbonate-producing enzymes called carbonic anhydrases.
"For the first time, we are able to use a drug that activates bicarbonate transport without affecting chloride transport, and see improvement in the disease," Harmon said. The results provide support for the hypothesis of experts in the field such as UCSD's Paul Quinton, PhD, who has written that increasing bicarbonate in cystic fibrosis tissues could be a relevant target for future therapies.
"The finding of the reduced PPAR-ã activating prostaglandin in cystic fibrosis is exciting since it could serve as a marker to identify which patients might benefit from treatment with PPAR-&gamm activating drugs," said Glass.
Additional contributors include Darren S. Dumlao and Edward A. Dennis of the Department of Chemistry and Biochemistry and Department of Pharmacology; Damian T. Ng, Department of Cellular and Molecular Medicine; and Kim E. Barrett and Hui Dong, Department of Medicine; all at the University of California, San Diego.
These studies were supported by grants from the National Institutes of Health and a Fellowship to Faculty Transition Award from the Foundation for Digestive Health and Nutrition to Harmon.
Debra Kain | EurekAlert!
Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University
How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung
Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.
Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....
Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.
The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
26.05.2017 | Life Sciences
26.05.2017 | Life Sciences
26.05.2017 | Physics and Astronomy