GRANT PROGRESS REPORT REVIEW
Grant:00945: Mucosal Gene Expression Profiles in Canine Inflammatory Bowel Disease
Principal Investigator:Dr. Albert E. Jergens, DVM, PhD
Research Institution:Iowa State University
Start Date: 6/1/2008End Date: 12/31/2011
Progress Report:30 month
Report Due: 11/30/2010Report Received:11/22/2010
Recommended for Approval: Approved
(Content of this report is not confidential. A grant sponsor s CHF Health Liaison may request the confidential scientific report submitted by the investigator by contacting the CHF office. The below Report to Grant Sponsors from Investigator can be used in communications with your club members.)
Original Project Description:
Background: Canine inflammatory bowel disease (IBD) is a chronic intestinal disorder likely resulting from the interaction between genes and environmental factors. While it is generally accepted that luminal bacteria play a critical role in provoking gut inflammation, genetic factors may also contribute to the bacterial-driven inflammatory response. Several susceptibility genes, such as NOD2/CARD15, have recently been identified in humans with IBD and provide a basis for the development of aberrant immune responses to bacteria in certain individuals. It is reasonable to hypothesize that susceptibility genes also affect clinical disease in dogs with IBD by negatively affecting the interaction with intestinal bacteria and/or their products. Genetic factors are thought to contribute to the pathogenesis of canine IBD as in humans. A role for luminal bacteria is suggested by observations that antibiotics reduce clinical signs, and by reports of increased bacterial numbers in intestinal biopsy specimens obtained from dogs with IBD. Given the recognized breed predispositions, genetic susceptibility to IBD is also likely, although studies are lacking.
Objective: The researchers are utilizing unique molecular biology tools to: (1) identify key genetic factors contributing to disease expression, (2) characterize gene expression profiles which may predict responsiveness to specific therapies, and (3) provide the framework upon which to facilitate identification of IBD susceptibility genes that predispose specific canine breeds to clinical disease.
Hypothesis: Gene expression profiles in intestinal tissue samples of dogs with IBD will provide comprehensive insight into altered gene expression patterns contributing to gut inflammation.
Objective 1: To investigate global gene expression patterns of inflamed intestinal tissues and normal control intestinal tissue using RNA microarrays. The differentially expressed transcripts will identify patterns associated with inflammation and host immune responses.
Objective 2: To utilize quantitative RT-PCR to confirm microarray data and validate unique gene expression signatures in dogs with IBD.
Objective 3: Evaluate the clinical, microbiologic, and anti-inflammatory effects of FOS
administration in dogs with IBD. (Appended Objective)
- Suchodolski, Js, Xenoulis, Pg, Paddock, Cg, Steiner, Jm and Jergens, Ae (2010) Molecular analysis of the bacterial microbiota in duodenal biopsies from dogs with idiopathic inflammatory bowel disease. Veterinary Microbiology. 142, 394-400. http://www.sciencedirect.com/science/article/B6TD6-4XNF6FB-
Report to Grant Sponsor from Investigator:
Canine inflammatory bowel disease (IBD) is a chronic intestinal disorder likely resulting from the interaction between genes and environmental factors. We propose to utilize unique molecular biology tools to: (1) identify key genetic factors contributing to disease expression, (2) characterize gene expression profiles which may predict responsiveness to specific therapies, and
(3) provide the framework upon which to facilitate identification of IBD susceptibility genes that predispose specific canine breeds to clinical disease. We are making good progress towards these goals as evidenced by the following:
We have collected samples from a representative heterogeneous population of 18 IBD
dogs for comparison to 6 healthy dog tissues.
We have carefully extracted the genetic material (RNA) from endoscopic samples which will be used in our gene profiling studies.
We have now evaluated gene expression profiles in the normal versus diseased dog groups using sophisticated statistical modeling to help us 'tease out' gene expression patterns which discern healthy versus diseased intestinal tissues. It is our expectation to identify specific genes which serve as biomarkers for diagnosing canine IBD and for monitoring the effects of therapy. We have now identified a grouping of 17 'marker' genes that may be more critically assessed in future studies.
We have noted that IBD dogs show differences in intestinal gene expression as compared to healthy dogs; and these differences in expression may help to explain the mechanisms of chronic inflammation in affected dogs.
We have preliminary evidence that changes in the intestinal bacteria accompany the abnormal gene patterns. It is our belief that this association should be explored more fully with additional studies; since this situation is identical to the association between people and their intestinal bacterial populations causing human IBD (i.e., Crohn's disease and ulcerative colitis).
We have now confirmed the expression patterns of select differentially expressed genes in diseased dogs using sophisticated molecular techniques. This suggests that the observations regarding gene expression patterns using the gene chips are accurate.
01485: Study of PLE/PLN (Protein-losing Enteropathy/Nephropathy) in Soft- coated Wheaten Terriers
Primary Investigator: Dr. Meryl P. Littman, VMD
Institution: University of Pennsylvania - School of Veterinary Medicine
Total Grant Amount: $50,000.00
In 1997 the Soft-coated Wheaten Terrier (SCWT) Club of America helped us start an Open Registry which lists dogs affected with familial diseases common to this breed such as inflammatory bowel disease (IBD), protein-losing enteropathy (PLE), protein-losing nephropathy (PLN), combination PLE/PLN, Addison's disease (AD), and juvenile renal disease/renal dysplasia (JRD). The 2009 update lists almost 1000 affected dogs, with the vast
majority affected with PLN, PLE, or PLE/PLN, in that order. These protein-losing diseases have had a devastating impact on the SCWT breed because: 1) there are no predictive tests, just
annual screening tests, 2) there is no age limit, so dogs might be used for breeding before they show illness, and 3) the mode of inheritance is unknown and appears complex. The PennVet SCWT DNA Bank contains more than 500 blood or tissue samples from affected dogs as well as geriatric (14 years or older) non-affected Wheatens. Most affected samples are from confirmed PLE and/or PLN cases, with diagnosis documented by blood, urine, and histopathology test results.
How are your donations put to work? We have funded, in cooperation with other SCWT groups, the following research projects.
In addition, we have assisted other DNA projects in the collection of samples by helping to fund these activities.
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The following letter from Meryl Littman explains the importance of participating in the cheek swab program. There is also up to date information about what is hoped will come from the swab information and insight into what may be the next steps along the reseaarch road. Click here for info on how to submit your swabs.