01265: Understanding Mechanisms Involved in Canine Autoimmune and Inflammatory Disorders
Grant Status: Closed
Autoimmune and inflammatory disorders including related pain have a major impact on the quality of life and longevity of dogs. Studies in humans highlight an important role for a molecule (termed P2X7 and present on white blood cells) in these disorders and pain. The role of P2X7 in these health problems is largely attributed to its ability to cause the release of immune hormones (termed interleukins) that drive immunity and inflammation. Thus, P2X7 is attracting considerable international interest as a therapeutic target in humans, with a number of P2X7 drugs currently being tested in clinical trials. We originally identified P2X7 on white blood cells from dogs (English Springer Spaniels). In the study funded by the AKC Canine Health Foundation we further investigated P2X7 on white blood cells from dogs, and its role in canine immunity and inflammation. As a result of this funding, we have characterised an artificial form of P2X7 (recombinant P2X7) made from an English Springer Spaniel. This recombinant P2X7 will serve as a useful tool to explore the role of P2X7 in dogs in future studies. Information from these studies may be used to develop drugs that can block canine P2X7, and thereby potentially reduce unwanted inflammation and related pain in dogs. As a result of this funding, we have also confirmed the presence of P2X7 and found previously undetected immune molecules in dog white blood cells. These molecules may provide additional future therapeutic targets in dogs. Moreover, we have found some of these molecules in dog kidney cells, which may be of therapeutic importance in canine kidney diseases. Finally, as a result of this funding, we have found that the relative amount of P2X7 in white blood cells various between dogs. This information will be used to determine if genetic or non-genetic factors contribute to this variation in P2X7, and whether it has any relevance to canine autoimmune and inflammatory disorders.
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Jalilian, I., Peranec, M., Curtis, B. L., Seavers, A., Spildrejorde, M., Sluyter, V., & Sluyter, R. (2012). Activation of the damage-associated molecular pattern receptor P2X7 induces interleukin-1β release from canine monocytes. Veterinary Immunology and Immunopathology, 149(1–2), 86–91. https://doi.org/10.1016/j.vetimm.2012.05.004
Jalilian, I., Spildrejorde, M., Seavers, A., Curtis, B. L., McArthur, J. D., & Sluyter, R. (2012). Functional expression of the damage-associated molecular pattern receptor P2X7 on canine kidney epithelial cells. Veterinary Immunology and Immunopathology, 150(3–4), 228–233. https://doi.org/10.1016/j.vetimm.2012.09.040
Spildrejorde, M., Bartlett, R., Stokes, L., Jalilian, I., Peranec, M., Sluyter, V., … Sluyter, R. (2014). R270C polymorphism leads to loss of function of the canine P2X7 receptor. Physiological Genomics, 46(14), 512–522. https://doi.org/10.1152/physiolgenomics.00195.2013
Wiley, J. S., Sluyter, R., Gu, B. J., Stokes, L., & Fuller, S. J. (2011). The human P2X7 receptor and its role in innate immunity. Tissue Antigens, 78(5), 321–332. https://doi.org/10.1111/j.1399-0039.2011.01780.x
Sophocleous, R. A., Sluyter, V., Curtis, B. L., Curtis, S. J., Jurak, L. M., Faulks, M., … Sluyter, R. (2019). Association of a P2RX7 gene missense variant with brachycephalic dog breeds. Animal Genetics. https://doi.org/10.1111/age.12884
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