2002 Research Protocols Supported by the ABCF and the AKC Canine Health Foundation

The following two new protocols were approved by the ABCF on May 6, 2002

Grant No. 2303: Molecular Analysis of Familial Ventricular Arrythmias in the Boxer Dog
Kathryn M. Meurs, DVM,PhD; Ohio State University

A heart muscle disease in the Boxer dog was initially documented in the 1980s and referred to as Boxer cardiomyopathy. Studies have confirmed that this is an inherited disease primarily characterized by an electrical disturbance in the heart that may lead to collapse and even sudden death. Unfortunately, many of the abnormalities do not become apparent until the dog is several years old and has already been used for breeding. There is therefore significant interest in developing a DNA test that could be performed before breeding. This study is the continuation of the study in which 268 Boxers were evaluated by physical exam, echocardiography, and Holter monitoring. Dogs have been classified as affected, equivocally affected, or unaffected: pedigrees and DNA samples have been collected. Linkage and candidate gene analysis will now be performed using canine markers and these DNA samples. This is the first step in identifying a genetic marker which might be used as a DNA screening test.

Grant No. 2306: Evaluation of the Geographical Variation in Familial Nature and Inheritance Patterns of Boxer Dogs with Familial Ventricular Arrhythmias
Matthew Miller, DVM, MS; Texas A&M University

Recent studies have confirmed that this disease is inherited and primarily characterized by disturbances in the cardiac electrical system, fainting episodes, and sudden death. Before investing significant time and resources into the development of a genetic test, it is imperative that the familial nature of the disease be well understood. Both studies that suggest a familial nature to Boxer ventricular arrhythmias have been performed in eastern regions of the United States. It is important to perform similar genetic evaluations in a unique geographical region to confirm that the familial nature and mode of inheritance are constant. This study will provide an increased understanding of the pattern of inheritance and genetic etiology of this disease within the United Stated as well as providing a bank of DNA samples from affected dogs.

Active Grant No. 22101: Development of Anti-Canine IL-2R? Antibodies Using CpG Oligodesoxynucleotide Vaccination
Stuart C. Helfand,DVM, University of Wisconsin, Madison.

Sponsor: Nestle Purina Company, American Boxer Charitable Foundation, Golden Retriever Club of America, Golden Retriever Foundation

This protocol could also be called, "the development of a magic bullet". Despite progress in treating canine lymphoma, most affected dogs eventually develop resistance to chemotherapy and succumb to their disease. In human medicine, a molecule on the surface of lymphoma cells, the subunit of the interleukin-2 receptor (IL-2R?). Recently, antibodies have been developed to deliver cellular toxins or radioisotopes directed against the malignant lymphoma cells, a strategy aimed at overcoming drug resistance. This technique is a form of so called immunotherapy which is being widely pursued in the treatment of human cancer. Dr. Hefland has succeeded in isolating the IL-2R molecule in Golden Retrievers and Rottweilers and now proposes a method to develop antibodies against this molecule. These antibodies then could be tagged with an appropriate cellular toxin or radioisotope to specifically target only the malignant lymphoma cells. This could prove to be a powerful tool in both diagnosis, prognosis, and treatment of canine lymphoma.

Grant No. 2214: Indentification of a 5-10Mb BAC Set for the Development of an Ordered CGH Array for Cancer Studies in the Dog and for the Refinement of Human-dog Comparative Maps
Co-Principal Investigator: Matthew Breen, PhD; Animal Health Trust, Great Britain/North Carolina State University
Co-Principal Investigator: Elaine A. Ostrander, PhD, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle Washington

Sponsor: American Boxer Charitable Foundation and Nestle Purina Petcare Company

The study of aberrant chromosome structure has significantly increased our understanding of the cause and progression of human cancers. Many cancers are common to both dogs and humans, in part neglecting the high degree of similarity in their genetic material and in their environmental exposure to carcinogens. The extent and identity of chromosome aberrations associated with canine cancer, however remains largely unknown. This is primarily due to the difficulty in identifying dog chromosomes by conventional means alone. Comparative genomic hybridization (CGH) is a technique that allows a comprehensive analysis of chromosome aberrations present within tumors. These researchers working at the Fred Hutchinson Cancer Center, where the first human bone marrow transplant was performed, have developed a technique for application to dog cancers and are obtaining valuable knowledge of dog chromosomes. Their technique, used often in the study of human cancer, will aim to identify a set of large insert clones that are evenly spaced, at small intervals, along all dog chromosomes. These clones will be used to generate an ordered microarray to replace chromosome-based analysis. This will significantly and rapidly advance the study of canine cancer, leading to improved diagnosis and prognosis and thus health and welfare.

Dr. William Truesdale, President of the American Boxer Charitable Foundation, requested that Dr. Paul Gerard write a brief paragraph on earlier protocols supported by the ABCF.

1. In addition to the continued evaluation and follow-up of the 268 Boxers in Dr. Kate Meurs original study of cardiomyopathy, the ABC Foundation has approved funds for an additional study of these animals. This is a continuation of the original study, demonstrating an inherited disease primarily characterized by an electrical disturbance in the heart (premature ventricular contractions.) This new study classifies the animals as affected, equivocally affected, or unaffected, based on Holter studies. Pedigrees and DNA samples have been collected and three-generation families have been identified. Linkage and candidate gene analysis will be performed using these DNA samples. The identification of a genetic marker linked to familial ventricular arrhythmias will be the first step in the development of a DNA screening test.

2. Dr. Matthew Miller at Texas A&M University will conduct a study duplicating some of Dr. Meurs earlier work. This study will be performed in a similar manner to Dr.Meurs study, but using dogs in a different geographical region to confirm that the familial nature and mode of inheritance are constant. Furthermore, Dr.Miller has worked with Dr. Meurs and will also be providing DNA samples for genetic analysis to provide further information on the genetic etiology.

3. In the area of canine and, in particular Boxer cancer, the Foundation is supporting a grant entitled "Heritable and Sporadic Genetic Lesions in Canine Lymphoma and Osteosarcoma" by Dr. Jaime Modiano, at the AMC Cancer Research Center. Lymphoma, a cancer of lymph glands, is among one of the most frequent malignant tumors occurring in Boxers, as well as many other breeds (accounting for approximately 20% of all canine tumors.) Osteosarcoma is the most common bone tumor in dogs. Previous work by Dr. Modiano has identified individual genes and larger regions within the genome that appear to be important in canine cancer. His project proposes to confirm the frequency and significance of these genetic anomalies, which may be heritable or sporadic, thus paving the way to apply this knowledge for clinical benefits by providing targets for treatment, and identify individuals at risk to develop these types of cancer or produce cancer-prone progeny.

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