Complete and Active AKC/CHF Grants
In 1998 the NEAA Board voted to participate in the AKC/CHF Donor Advised Fund program. Since that time, donations to that fund have been authorized for use toward several research projects. Below is a list of completed, closed and active grants as well as an abstract describing each project.
Amy McNeill DVM PhD
Problem: Novel cancer treatments are needed to minimize patient discomfort caused by cancer therapy and eliminate failure of current treatment modalities. The use of oncolytic viral vectors is an exciting therapeutic option that deserves further study.
This project is designed to determine if the poxvirus, myxoma virus (MYXV), can be used to eliminate cancer cells and prevent the spread of tumors throughout the body. Poxviruses have several characteristics that make them ideal cancer therapeutics: 1) they target neoplastic lesions where leaky vessels are formed; 2) they are easily engineered to express antitumor agents; 3) they elicit a strong immune response which can be used to target abnormal cells; and 4) they are effectively cleared from the body by antibodies, preventing latent or recurrent infection.
MYXV is a poxvirus that does not cause disease in any animal except the rabbit. However, MYXV does grow in some cancer cells. Since MYXV only grows in abnormal cells, virus replication in healthy tissue should not occur. The lab has tested several canine tumor cell cultures and many support growth of MXYV. We also created a genetically altered MYXV that no longer causes disease in rabbits, but causes increased numbers of canine cancer cells to die as compared to wild-type MYXV infection.
This project aims to evaluate the anticancer effects of MYXV in mouse models of canine cancer. If the tumors can be reduced in size or eliminated, these studies may lead to the use of genetically modified poxviruses as cancer treatments in companion animals.
Leptospirosis is a disease of dogs and humans that can be fatal, occurs worldwide, and originates from wildlife. The bacteria causing disease has many different strains, each coming from a different wildlife reservoir. Although vaccination of dogs against canine leptospirosis has taken place for decades, novel and potentially emerging vaccine-resistant strains from wildlife have been detected recently. As our society increasingly encroaches on wildlife habitat, there is greater risk for dogs to acquire infection from contact with infected wildlife. No current spatial or risk analysis has been performed for canine leptospirosis in the western US. Moreover, diagnostic tests that are rapid, sensitive, quantitative, and capable of discriminating among strains are lacking, which hinders our ability to manage individual cases and understand the epidemiology of this disease. Our study aims to determine risk factors for, and clinical characteristics of, modern leptospirosis in dogs by retrospective analysis of two large databases; generate a statistical risk model and use GIS-based mapping to detect spatial clustering of cases; develop a reliable, sensitive diagnostic method to identify active infections and differentiate among strains of Leptospira interrogans; and prospectively sample dogs in high risk areas in order to acquire isolates for future pathogenesis study and molecular genotyping, and to evaluate acute active infections of individual dogs to allow for successful treatment. Results from our study will provide valuable information that will improve success of patient management, reduce risk of infection to other dogs and humans, and inform future surveillance and vaccine efforts to improve canine health.
Grant 00972: Identification of Mutations Associated with Hereditary Cataracts in Northern Breeds
Principal Investigator: Dr. Cathryn Mellersh, Ph.D.
Research Institution: Animal Health Trust
Report to Grant Sponsor from Investigator:
Our study aimed to investigate the genetic cause of hereditary cataract (HC) in Northern breeds. We have collected samples from 228 dogs affected with bilateral cataract (both eyes) and 300 dogs with a clear eye examination from 15 Northern breeds, initially screening known human cataract-causing genes in 66 dogs from two of these breeds. We used a panel of 39 markers near to 20 genes involved in human inherited cataract and found no evidence for association of any markers with HC in the two breeds. Using genome-wide association (GWA) study (whole genome scanning) approaches we conducted an initial analysis of HC in the Finnish Lapphund, Icelandic Sheepdog, Samoyed and Siberian Husky. For the Samoyed we found evidence for an association with HC on chromosome 7, but no associations were identified in the other three breeds. These initial results suggested that HC in Northern breeds is not caused by a single gene mutation and may have a more complex genetic background. This finding is not entirely surprising when it is considered that to date only a single gene, HSF4, has been implicated in the development of HC in the dog despite the fact that close to 100 breeds are known to be affected by the condition. To detect mutations in numerous genes requires analysis of a larger number of samples using a rigorous definition for affected dogs (‘cases’) and unaffected dogs (‘controls’). Therefore for our final investigation we concentrated our efforts on four breeds that display a clinically similar form of HC and for which we have sufficient numbers of cases and controls for analysis. We have conducted a GWA scan of HC in these four breeds—the Alaskan Malamute, Siberian Husky, Karelian Bear Dog and Samoyed—using an updated high-density genome scanning array comprising around 174,000 markers spanning the DNA. Our initial analyses of these data are promising and we have found evidence of HC-associated regions for at least three of the breeds. We are currently investigating these association signals and we aim to design and conduct further studies to attempt to pinpoint the causal mutations.
Closed Grant No: 386 — Elucidation of the Genetic Defect in Familial Renal Disease in the Norwegian Elkhound
Researcher: Dr. Peter Leegwater – University of Utrecht, The Netherlands (University) Dr. Danika Bannasch – University of California, Davis (University)
Abstract: Familial Renal Disease is a hereditary disease in the Norwegian Elkhound that causes kidney failure at a young age. Unfortunately, the disease is progressive and incurable, and the Elkhound will eventually die from it. Diagnosing the disease is difficult because it requires a kidney biopsy and because of a variable expression and a late onset of signs of illness. This is the reason why dogs are often bred before they show any symptoms; the genes involved can, unknowingly be passed on to the next generation. A DNA test would make it much easier to unequivocally test the Elkhounds before breeding. In this way only healthy dogs could be used for breeding, and the disease could be eradicated from the population. In this research a family of 72 Norwegian Elkhounds is going to be tested for Familial Renal Disease. A DNA sample and the disease status of each dog will be used in a genome wide DNA study, to find a marker for this disease. Aim is to develop a DNA linkage test and, ultimately, a DNA mutation test. Identification of the causative gene will lead to a better understanding of the process that causes Familial Renal Disease and similar canine kidney disease.
Completed Grant No: 1663 — Identifying the Genetic Casue of Canine Progressive Rod-cone Dysplasia (PRCD Type of PRA)
Researcher: George J. Brewer, MD – University of Michigan (University)
Researcher: George J. Brewer, MD – University of Michigan (University) Abstract: Using both cloning and DNA sequencing, researchers ruled out five genes (of an identified 31 candidate genes) as the causative gene for Progressive Rod-Cone Disease (PRCD), a form of Progressive Retinal Atrophy, an inherited disease that leads to blindness. With continued research, the cloning and sequencing of the other 26 candidate genes can be completed. Once the genetic cause and mutation are found, direct DNA tests, which are more accurate than linkage tests, can be developed to help breeders make breeding decisions in order to reduce or eliminate this disease. All 31 candidate genes were known to be in the region of the chromosome linked to PRCD by researchers at Cornell.
Completed Grant No: 2012 — Development of PCR Multiplexed Canine Marker Panels for the Purposes of Genome Screening and Linkage Analysis
Researcher: Marcia Eggleston, PhD – University of California, Davis (University)
Abstract: A number of tests have been developed to screen for affected or carrier animals with genetic diseases. The development of many of these tests was possible due to the availability of information regarding similar disorders in humans. The majority of disorders affecting purebred dogs have no known counterpart in humans and therefore no candidate gene. However, an indirect test that screens for a strong association of a microsatellite DNA marker with a disease phenotype can be incorporated in a simple diagnostic test for carriers of that trait. The ultimate goal of the research is to design marker panels containing a minimum of 300 microsatellite markers covering all the linkage groups or chromosomes of the canine genome. The Veterinary Genetics Laboratory has completed panels containing 100 markers with known map locations. This project will incorporate at least 200 additional markers that will then represent the entire canine genome and allow effective screening for linkage or markers to disease gene(s).
Closed Grant No: 2434 — Recombinant Thyrotropin (TSH): Standard for the Next Generation of Canine TSH Immunoassays with Improved Sensitivity
Researcher: Duncan Ferguson, DVM, PhD – University of Georgia (University)
Abstract: Hypothyroidism, a failure of the thyroid gland, is the most common hormonal abnormality in dogs, causing a variety of medical problems in many breeds, including hair loss and skin infections. The measurement of serum levels of the pituitary hormone thyrotropin (TSH) has been used as a reliable and sensitive screening test for ghyroid glandular insufficiency in human medicine for many years, but the first generation assays for canine TSH (cTSH) are missing as many as one out of four cases by hypothyroidism, resulting in no improvement in diagnostic sensitivity compared to total T4 measurement. Furthermore, the available assays have not been sensitive enough to distinguish low values of cTSH from those in the normal range. Towards the goal of improving current and future immunoassay sensitivity based upon a pure recombinant canine TSH(cTSH) hormone standard, our laboratory has succeeded in cloning and sequencing the two peptide subunits of canine TSH and have expressed them in small quantities. Using techniques recently developed in our parallel work on equine TSH, we plan to express and purify recombinant canine TSH in high quantities and validate its use as a pure immunoassay standard to facilitate its worldwide use.
Completed Grant No: 2616 — Molecular Analysis of Contributory Factors of Osteoarthritis in Canine Hip Dysplasia
Researcher: Alpana Ray, PHD – University of Missouri, Columbia (University)
Abstract: Hip Dysplasia is a common disease of dogs that ultimately leads to osteoarthritis (OA), a serious debilitating condition, which at present, is treated by symptomatic management of pain. Accidental injuries also lead to the development of OA. Cartilage degeneration is fundamental to the pathogenesis of OA. We propose to study the transcriptional control of MMP-1, a major enzyme involved in the degradation of articular cartilage. Expression of MMP-1 gene and the corresponding protein is markedly increased under osteoarthritic condition. Because cytokines like IL-1 and TNF increase expression of MMP-1 and biomechanical factors also influence its expression in osteoarthritic, unstable joints, the objectives are to understand what components of the promoter region of canine MMP-1 gene are influenced by these factors. At present no data is available on canine MMP-1 gene regulation. This proposal is aimed towards understanding the regulation of canine MMP-1 gene expression in response to biomechanical stress and cytokines by isolating canine MMP-1 gene, identifying the regulatory elements in the promoter responsive to biomechanical stress and cytokines, and analyzing MMP-1 expression in chondrocytes of articular cartilage form normal and osteoarthritic dogs with the intent to develop novel therapeutic drugs to combat this disease.
The above was last updated March 2011