Our ability to study the immune response or develop or test new drugs to treat various diseases in dogs is restricted by our reliance on low numbers of naturally occurring cases in pet animals and the high cost and logistical difficulties of inducing disease in research animals. Genetically engineered and immunodeficient mice are a valuable tool for research studies into human and animal disease. Highly immunodeficient mice, also known as NSG mice, lack mature T, B, and NK cells, and have impaired innate cell responses due to a deficiency in the common gamma chain of many cytokine receptors. NSG mice have allowed for the development of patient-derived xenograft (PDx) models, where cells or tissues from humans or dogs, e.g. tumors from patients, can be transplanted into mice to study disease pathophysiology and test new therapeutic approaches. However, a major drawback of these mice is their lack of immunity; the immune system has a major influence on disease development, progression and treatment responses. This limitation has been overcome with ‘humanized’ mice, in which immunodeficient mice are given human hematopoietic stem cell (HSC) transplants to reconstitute a predominantly human immune system in the mouse. Such humanized mice have been used to study immune responses and pathophysiology of various human diseases, including cancer, infections, immune-mediated disease, as well as physiologic processes like wound healing. Unlike our human counterparts, we lack a robust platform to test hypotheses and study canine diseases, which are influenced by the immune system, in a controlled experimental fashion. We propose to develop a canine reconstituted immune system (CRIS) in NSG mice, thereby creating a ‘caninized’ analog to humanized mice. This will be accomplished by transplanting harvested canine HSC into NSG mice. Mice will be monitored to document health and successful engraftment. CRIS mice will be characterized using standard clinical pathologic and histologic methods and also tested for canine immune functionality via ovalbumin challenge. We have leveraged the combined expertise of pathologists, immunologists, the Innovation Laboratory, and Progressive Assessment for Therapeutics (PATh) PDX facility to facilitate success. If we are successful, CRIS mice will be a novel research tool for the entire Cornell scientific community (and beyond) that will fuel basic research in immunology and infectious disease in dogs, serve as a backbone for testing new combinatorial therapies and immunotherapeutic compounds for various diseases in dogs, and help propel us to the next level of basic, preclinical, and translational canine research.