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Maximizing the Benefits of Genomic Research on Clara Cell Secretory ProteinJuly 2012

Drs. Beinzle, Betteridge and Hayes Report on Research Video QR Code to research video

by Barbara Sheridan

In a major step towards combating issues affecting equine reproduction and respiration, researchers at the University of Guelph have identified a protein called Clara cell secretory protein (CCSP) that may assist in developing better defence systems when it comes to treatment and prevention. The initial release of the horse genome database in 2007 has provided scientists with completely new information pertaining to horses’ genes. This, along with the associated technologies in identifying proteins controlled by the genes, has since then greatly benefitted veterinary researchers working on equine health and disease.

Working as a main anti-inflammatory protein, CCSP appears to play a critical role in the defence against airway disease in mammals, and Dr. Dorothee Bienzle, Professor in the Department of Pathobiology at the Ontario Veterinary College (OVC), is currently studying the effects of this key protein and the role it can play in determining and treating Recurrent Airway Obstruction (RAO) in horses.

A chronic inflammatory lung disease, RAO is commonly referred to as heaves and affects up to 50% of horses worldwide. It is typically caused by an allergic-type of reaction following repeated exposure to environmental substances associated with poor quality hay or bedding. Even though this disease has been recognized for centuries, current treatment for horses with RAO is limited, resulting in affected horses being unable to race or perform as show horses.

While environment plays a key role in RAO, Bienzle believes that this disease could also develop in older horses that suffered severe respiratory virus infections as youngsters. Even after overcoming the viral infection, a certain proportion of these horses end up developing this asthma-like condition later on in life, which is then very difficult to treat and is essentially impossible to reverse.

“We believe that some horses that suffer severe viral respiratory infections as youngsters, with organisms such as herpesvirus, influenza virus, or rhinovirus, develop a condition called ‘inflammatory airway disease’ (IAD),” says Bienzle. “Basically, the lining of the airways becomes inflamed, and some horses that have IAD never ‘reset’ their airway epithelium to the right balance of reacting to environmental stimuli and suppressing reactions. We believe those horses that remain prone to exaggerated inflammatory response are very likely to develop heaves.”

Bienzle has discovered that the CCSP that is naturally produced in the lower bronchi plays an important role in counteracting lung inflammation in horses with RAO. In identifying the role of the protein they are studying, Bienzle explains that this will help researchers to better understand how the airway defends itself against environmental stimuli, enabling them to properly diagnose and better treat the condition. “We recognize CCSP as a main anti-inflammatory protein, but we don’t really know how it works,” explains Bienzle. “We would like to know whether it works in defending the airway epithelium (tissue which lines the respiratory tract) against viruses, inhaled particles, bacteria and/or other stimuli. We would also like to know how it decreases airway inflammation.”

While it has been found that the majority of CCSP is produced in the horse’s conducting airway, University of Guelph researchers have also discovered important changes pertaining to key proteins that are involved in similar interactions between the uterus of the mare and the early developing embryo. Dr. Keith Betteridge, Department of Biomedical Sciences, and Dr. Tony Hayes, Department of Pathobiology, both professors at the OVC, came together eight years ago with a common goal of reducing early pregnancy loss in mares.

Nearly 17% of diagnosed pregnancies fail to produce a foal, and about 60% of the failures occur within the first five weeks of pregnancy. Both Betteridge and Hayes are focused on identifying the changes in molecules that are produced in the uterus in mares, including proteins that play a critical role in the failure of early pregnancy, as well as in infertility due to inflammatory processes. They feel that identifying these key molecules will assist in the development of early diagnostics and in creating new treatments for infertility.

“It would be very nice to be able to reduce the numbers of failed pregnancies,” explains Betteridge. “And to be more specific, when we have systems that age the horse from the 1st of January for example, it is very important to get mares pregnant early in the season; being able to prevent pregnancy loss would go a long way towards meeting that goal.” Genomic research has equipped the veterinary researchers with the ability to identify many proteins by mass spectrometry and has revolutionized their ability to analyze the proteins in detail, as they study fertility and infertility in horses. It is details like these that guide researchers to the next ‘growing point’ of the continuous research process. The researchers note that there is much more to learn about early pregnancy, and by studying CCSP, they will have a better of idea of what can go wrong in early pregnancy.

“If we are able to identify the key molecules that are produced in mares,” says Hayes, “We will be able to do two things. We will be able to hopefully develop a test which will help us measure the potential for that particular mare to get pregnant and may be able to use particular treatments that counteract the nasty effects of some of these proteins and therefore settle down the inflammatory response and make pregnancy more likely to occur earlier.”

While genomic research has revolutionized the ability to identify the production of thousands of proteins, Hayes notes it can also be bewildering at times because researchers are confronted suddenly with huge amounts of new information about what’s happening during these critical events. It then takes some time to analyze all of these activities and the locations of protein production.

“There are a lot of the proteins controlled by these genes that have been identified in parallel with what has been known in other species, but still there are many, many genes that are poorly understood in the horse, and I think it will be another five or ten years before the full depth of genomic information will be available for researchers like us,” says Hayes. “But nonetheless, there are many, many helpful items that we can follow now with regard to reproductive health that will be of benefit to the industry.”

Funding for these research projects have been provided by Equine Guelph, Grayson Jockey Club Research Foundation, Natural Sciences and Engineering Research Council of Canada (NSERC), Ontario Ministry of Agriculture, Food and Rural Affairs (OMAFRA) and the University of Guelph.

Funding for the Report on Research and Help for Horse Owners videos has been provided by the Knowledge Translation and Transfer Program under the OMAFRA-U of G Partnership.