Abstract:
Hemangiosarcomas (HSA) is a common and fatal cancer in dogs for which there is no effective treatment. Despite surgery and intensive chemotherapy, the median survival time for dogs diagnosed with HSA is little more than six months. From our own studies on canine cancer, expression of the enzyme telomerase allows cancer cells to become immortal and has emerged as a central and near universal marker of cancer, making it a candidate target for novel therapies. In this study we will explore the value of telomerase inhibition to treat HSA using the novel mechanism of RNA interference (RNAi). Our hypothesis is that potent inhibition using this technique will inhibit the immortal phenotype of the cancer cells and cause them to die. However, it is possible that a combined approach, targeting two molecular pathways, may offer greater therapeutic benefit. Consequently, we will also explore the potential synergism of combining telomerase inhibition with an alternative inhibitor of a further mechanism involved in cancer (receptor tyrosine kinase inhibition) on targeting this highly malignant tumor. In this we will use in vitro cell culture techniques for initial inhibition studies followed by studies in a novel canine HSA model system to ascertain the potential clinical merit of this approach for dogs with HSA.

Ohio State University (University)
Completed Grant No: 1428: Inheritance Patterns and Molecular Genetic Analysis of Doberman Pinschers and Boxer Dogs with Familial Dilated Cardiomyopathy
Disease: Heart Disease
Sponsors: American Boxer Charitable Foundation, Great Dane Club of America
Researcher: Kathryn Meurs, DVM, PhD, DACVIM
Breeds: Boxer, Doberman Pinscher

Abstract:
This study found that ventricular arrhythmias in Boxers are inherited as an autosomal dominant trait. Researchers found that asymptomatic Boxers have frequent ventricular premature complexes (VPCs), a specific type of irregular heartbeat that is a common form of ventricular arrhythmia. They determined that a two- to three-minute electrocardiogram (ECG) is a poorly sensitive indicator of VCPs, and instead recommend the use of a 24-hour ambulatory ECG (Holter monitor), even on asymptomatic Boxers. In studying Doberman Pinschers, they ruled out some potential candidate genes for study by demonstrating that two specific proteins and a specific gene that are abnormal in some humans with dilated cardiomyopathy (DCM)¿a primary heart muscle disorder that can cause the heart to beat erratically¿are normal in Dobermans with DCM. Linkage analyses for both Boxers and Dobermans continue.

Abstract:
Heart disease in the Boxer was initially documented in the 1980s and referred to as a Boxer cardiomyopathy. More recent studies have confirmed that this disease is inherited and is primarily characterized by disturbances in the cardiac electrical system, fainting episodes and sudden death. The inherited nature of the disease has led to increased interest in the screening of dogs for the disease by electrocardiogram, ultrasound and Holter monitoring prior to using them for breeding. However, the interpretation of the results is difficult, since many adult Boxers have some abnormalities detected on at least one of the tests and there is no available information regarding the relationship between these findings and the likelihood of development of clinical signs. The objective of this study is to evaluate the correlation between specific cardiac parameters (Ventricular Premature Contractions (VPC) number, grade of arrhythmia, heart rate, etc.) detected by electrocardiogram, ultrasound, and Holter monitoring and the development of clinical signs including fainting, sudden death and congestive heart failure in 130 adult Boxers previously diagnosed with heart disease.

Active Grant No: 228: A Comparative Evaluation of the Concealed and Overt Forms of Arrhythmogenic Right Ventricular Cardiomyopathy: Risk Factors Associated with the Development of Symptoms in Dogs with Arrhythmogenic Right Ventricular Cardiomyopathy
Diseases: Heart Disease
Sponsors: American Boxer Charitable Foundation
Researcher:
Kathryn Meurs, DVM, PhD, DACVIM
Breeds: Boxer

Abstract:
The clinical syndrome characterized by ventricular arrhythmias, collapsing episodes, sudden cardiac death and sometimes, heart failure in the Boxer dog was previously referred to as Boxer Cardiomyopathy. More recent studied have demonstrated striking similarities, including the inheritance, to a human disease called Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). The familial nature as well as the devastating outcome of the disease has lead to significant interest in developing screening methods for asymptomatic dogs prior to use for breeding. Screening is to develop a blood test are underway. However, although these screening methods will detect affected dogs, it appears that not all dogs that are affected will ever develop clinical signs. Unfortunately, these dogs may be removed from showing or breeding programs because of their abnormal status. The objective of this study is to evaluate asymptomatic and syncopal Boxers for findings that may relate to the development and presence of symptoms, including ventricular premature couple number, grade of arrhythmia, left and right ventricular size and function, BNP, Troponin I and family history.

Completed Grant No: 2303: Molecular Analysis of Familial Ventricular Arrhythmias in the Boxer Dog
Disease: Heart Disease
Sponsor: American Boxer Charitable Foundation
Researcher: Kathryn Meurs, DVM, PhD, DACVIM
Breed: Boxer

Abstract:
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 collapsing episodes and sudden death. There is increasing demand for a screening test that could be used to evaluate dogs for the disease before they are selected for breeding purposes. Unfortunately, many of the clinical abnormalities do not become apparent until the dog is several years old. Therefore, there is significant interest in developing a DNA test that could be performed before a dog is selected for breeding. The study proposed here is a continuation of a study in which 268 Boxers were evaluated by physical examination, echocardiography and ambulatory electrocardiography. Dogs have been classified as affected, equivocally affected or unaffected; pedigrees and DNA samples have been collected. Three-generation families have been identified. Linkage and candidate gene analysis will now be performed using canine markers and these DNA samples. The identification of a genetic marker linked to familial ventricular arrhythmias will be the first stem pin the development of a DNA screening test.

Completed Grant No: 2429: The Assessment of Ejection Murmurs in the Boxer Dog
Disease: Heart Disease
Sponsor: American Boxer Charitable Foundation
Researcher: Kathryn Meurs, DVM, PhD, DACVIM
Breed: Boxer

Abstract:
Subvalvular aortic stenosis (SAS) is a common, inherited birth defect of the heart. SAS often affects Boxers and impacts breeding programs. Severely affected dogs are at risk for heart failure, heart infection, and sudden death. Veterinarians usually identify SAS by listening for a heart murmur. In over 50% of Boxers, a murmur compatible with SAS is found, prompting sophisticated ultrasound imaging (echocardiography) and blood flow studies (Doppler). Even these tests may not distinguish a stressed or excited, but otherwise normal dog, from one with mild SAS. This uncertainty is a source of frustration to Boxer breeders. The proposed study explores causes of soft murmurs and increased blood velocities in Boxers. Extensive noninvasive ultrasound studies comparing affected and unaffected dogs are proposed. Furthermore, the origin of these soft murmurs is investigated in a subgroup of Boxers. In these clinical evaluations we will employ ¿gold standard¿ methods of X-ray contrast angiography (die), direct (catheter) measurement of blood flow in the heart, and recording of heart murmurs within the heart and blood vessels. We hope to answer the pivotal questions: are these soft murmurs and increased blood velocities really due to SAS, or do they simply represent a normal physiologic event?

University of Illinois (University)
Active Grant No: 360-A: Genome Expression Profiling: Canine Cardiomyopathy and Degenerative Mitral Valve Disease
Disease: Heart Disease
Sponsor: Not Listed
Researcher: Mark A. Oyama, DVM, DACVIM
Breeds: Boxer, Doberman Pinscher

Abstract:
Canine cardiomyopathy and degenerative valve disease have proven to be highly complex conditions, with multiple potential etiologies, elaborate and interrelated pathophysiologic mechanisms, and a diverse phenotypic expression. The analysis of such complex systems would benefit from a global assessment of gene expression. Because gene expression is the primary regulator of cell function, expression profiling in diseased subjects could provide valuable information about the response of the cell to injury, activity of physiologic pathways, and possible etiologies. Expression profiling may also enable the identification of diagnostic or prognostic markers, thereby improving the clinical management of disease. To this end, genomic microarrays represent an emerging technology that can assess the activity to profile the genome on a global scale. Using a newly developed canine gene microarray, we seek to profile genome expression in ventricular tissue of dogs with cardiomyopathy in mitral valve tissue in dogs with age-related mitral disease, and to compare the genomic expression in these populations with controls from an age and breed matched population. Genomic profiling will provide a molecular portrait of cardiomyopathy and degenerative valve disease.

Washington State University (University)
Pending Grant No: 440: A Molecular Evaluation of Two Forms of Canine Cardiomyopathy
Disease: Heart Disease
Sponsors: American Boxer Charitable Foundation, Doberman Pinscher Club of America
Researcher: Kathryn Meurs, DVM, PhD, DACVIM
Breeds: Boxer, Doberman Pinscher

Abstract:
Cardiomyopathy is the second most common heart disease diagnosed in the dog. The two most common forms of canine cardiomyopathy are dilated cardiomyopathy (DCM) and Arrhythmogenic right ventricular cardiomyopathy (ARVC). Both are adult onset, familial diseases that frequently progress to sudden death and/or heart failure. We hypothesize that these diseases can each be mapped to a separate, location on a canine chromosome. The objective of this study is to perform a genome wide scan using DNA samples from families of Doberman Pinschers with DCM and Boxers with ARVC. Canine genetic markers will be evaluated to identify a chromosomal location linked to each of these diseases. The identification of a chromosomal location linked to the disease will allow additional evaluation of this region for a gene responsible for the disease and may be useful for the identification of at risk dogs even before the causative gene is identified.

University of Georgia (University)
Active Grant No: 2434: Recombinant Thyrotropin (TSH): Standard for the Next Generation of Canine TSH Immunoassays with Improved Sensitivity
Disease: Thyroid Disease
Sponsor(s): Airedale Terrier Club of America, Akita Club of America, Inc., American Belgian Malinois Club, American Boxer Charitable Foundation, American German Shepherd Dog Charitable Foundation, Borzoi Club of America, Clumber Spaniel Club of America, Collie Health Foundation, Dalmatian Club of America Foundation, Inc., English Setter Association of America, Golden Retriever Foundation, Italian Greyhound Club of America, Keeshond Club of America, Komondor Club of America, Miniature Pinscher Club of America, Inc., Norwegian Elkhound Association of America, Inc., Petit Basset Griffon Vendeen Club of America, Portuguese Water Dog Foundation, Rhodesian Ridgeback Club of the United States, Scottish Terrier Club of America Health Trust Fund, Yorkshire Terrier Club of America Foundation, Inc.
Researcher: Duncan Ferguson, DVM, PhD
Breeds: Airedale Terrier, Akita, All (non-specified), Belgian Malinois, Borzoi, Boxer, Clumber Spaniel, Collie, Dalmatian, English Setter, German Shepherd Dog, Golden Retriever, Italian Greyhound, Keeshond, Komondor, Miniature Pinscher, Norwegian Elkhound, Petit Basset Griffon Vendeen, Portuguese Water Dog, Rhodesian Ridgeback, Scottish Terrier, Yorkshire Terrier

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 thyroid glandular insufficiency in human medicine for many years, but the ¿first generation¿ assays for canine TSH (cTSH) are missing as many as 1 out of 4 cases of 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.