These studies are aimed primarily at the investigation of new approaches to understanding and treating the corresponding disease in human patients. Current studies include comparative mapping of disease genes in the dog, studies of the pathogenesis of genetic diseases in dogs and cats, and gene therapy studies in mice, cats, and dogs. This work contributes basic knowledge needed in both veterinary and human medicine to define the molecular nature of genetic diseases, and to understand the intermediate steps between the disease gene and the clinical and pathologic phenotype in affected individuals. These are primarily conducted through individual research grants, mostly from NIH. Many of these grants involve collaborations among the CCMG laboratories.

This research concentrates on the identification of naturally occurring genetic diseases of animals and characterization of these diseases at the clinical, pathologic, and molecular genetic levels. One objective is to provide the basic knowledge needed to provide useful animal models of disease for further investigation. Potential new genetic diseases are diagnosed and initially characterized under an NCRR Center Grant. The second objective is to use the research information to accurately diagnose and reduce the frequency of genetic disorders within the animal populations in which they occur. This is done in the Josephine Deubler Genetic Testing Laboratory, utilizing a variety of DNA and other tests, as a service to the veterinary, and dog and cat breeding communities. A comprehensive computerized knowledge base on genetic diseases of the dog, The Canine Genetic Disease Information System, is a computerized database that has been developed by Dr. D.F. Patterson and is expected to assist veterinarians, geneticists, and dog breeders in eliminating disease-producing genes from breed populations.

Finding and Characterizing Disease Genes in Animals

The development of methods to map mammalian genomes has revolutionized the approach to identification, isolation and characterization of the mutations that underlie genetic diseases. Recent advances in genome sciences methods have made it more practical to use this approach in the dog and cat. The detection and study of a large variety of disorders with recessive and complex patterns of inheritance is greatly facilitated in the dog and cat because there is enough periodic inbreeding to reveal these defects, but the alleles that confer susceptibility still exist in sufficient frequencies in these populations to be available for study. Breeds of dogs and cats have the same advantages for such studies as human genetic isolates, but the number and diversity of the isolates (breeds) are many times greater than is found in the world’s human population. This is a resource in comparative medical genetics that is waiting to be mined for the purpose of better understanding of human disease, as well as for the improvement of animal health. This effort in the CCMG is focused on avenues of research where the animal models offer unique ways to investigate the genetics and biology. The diseases to be studied are selected for the medical characteristics, the underlying pathology, where the inheritance is sufficiently well documented that a focused investigation can be performed, and where scientific progress can be accelerated by studying the animal disease. To learn more, visit the Penn Genome Frontiers Institute.

Understanding the Cellular and Molecular Basis of Pathology

Although new disease-causing genes are being identified at a rapid rate, there are great gaps in knowledge of how the mutant genes cause the observed clinical and histopathological abnormalities. Animals with specific genetic diseases constitute a major resource for studying the natural history of rare disorders. Because cohorts of sufficient sizes can be studied, various stages of disease progression can be evaluated. Many studies on animal models have been instrumental in improving understanding of the human disease, where it is often impossible to obtain affected tissues during the course of the disease. In addition, a thorough understanding of the molecular and cellular abnormalities of each disease is critical for the rational design of new therapies.

Using Gene Based Approaches to Treatment

Advances in molecular biology are being developed into entirely new methods of treating disease. The concept of gene therapy for single gene inherited disorders is compellingly simple: treat a disease at the fundamental level of the DNA defect by inserting a normal copy of the gene into the affected cells of a patient to correct the biochemical deficiency responsible for the symptoms. However, after more than15 years of investigation by many laboratories, this goal remains elusive. It has been particularly difficult to scale up the methods from rodents to large mammals, including humans. The animal models being studied by CCMG investigators provide experimental platforms for understanding the problems of delivering genes successfully to a large mammal under actual disease conditions. In veterinary clinical medicine the best treatment for these very rare disorders will be to remove the mutant allele from the breeding stock. However, there are a number of diseases of veterinary importance where gene transfer methods may be applicable, e.g. cancers, degenerative joint disease in horses, neurologic abnormalities, and common metabolic diseases such as diabetes. Effective application in a clinical setting will depend on having a thorough understanding of the underlying biochemical, cellular, and pathologic mechanisms of each disease.

Direct viewing of Life Processes, Pathology and Treatment

Biological imaging using noninvasive methods is changing the landscape not only of clinical medicine but of research into biological processes in their natural settings. CCMG investigators use techniques such as NMR to study the progression of disease and responses to treatments and to gain new insight into pathologic mechanisms. Future research in this area will be done in close collaboration with the Metabolic Magnetic Resonance Research and Computing Center and the Department of Radiology in the School of Medicine to take advantage of the infrastructure, expertise, and instrumentation that is available to the biomedical community at Penn.