Understanding hereditary diseases using the dog and human as companion model systems.
Ontology highlight
ABSTRACT: Animal models are requisite for genetic dissection of, and improved treatment regimens for, human hereditary diseases. While several animals have been used in academic and industrial research, the primary model for dissection of hereditary diseases has been the many strains of the laboratory mouse. However, given its greater (than the mouse) genetic similarity to the human, high number of naturally occurring hereditary diseases, unique population structure, and the availability of the complete genome sequence, the purebred dog has emerged as a powerful model for study of diseases. The major advantage the dog provides is that it is afflicted with approximately 450 hereditary diseases, about half of which have remarkable clinical similarities to corresponding diseases of the human. In addition, humankind has a strong desire to cure diseases of the dog so these two facts make the dog an ideal clinical and genetic model. This review highlights several of these shared hereditary diseases. Specifically, the canine models discussed herein have played important roles in identification of causative genes and/or have been utilized in novel therapeutic approaches of interest to the dog and human.
Project description:Around the world, human populations have experienced large increases in average lifespan over the last 150 years, and while individuals are living longer, they are spending more years of life with multiple chronic morbidities. Researchers have used numerous laboratory animal models to understand the biological and environmental factors that influence aging, morbidity, and longevity. However, the most commonly studied animal species, laboratory mice and rats, do not experience environmental conditions similar to those to which humans are exposed, nor do we often diagnose them with many of the naturally occurring pathologies seen in humans. Recently, the companion dog has been proposed as a powerful model to better understand the genetic and environmental determinants of morbidity and mortality in humans. However, it is not known to what extent the age-related dynamics of morbidity, comorbidity, and mortality are shared between humans and dogs. Here, we present the first large-scale comparison of human and canine patterns of age-specific morbidity and mortality. We find that many chronic conditions that commonly occur in human populations (obesity, arthritis, hypothyroidism, and diabetes), and which are associated with comorbidities, are also associated with similarly high levels of comorbidity in companion dogs. We also find significant similarities in the effect of age on disease risk in humans and dogs, with neoplastic, congenital, and metabolic causes of death showing similar age trajectories between the two species. Overall, our study suggests that the companion dog may be an ideal translational model to study the many complex facets of human morbidity and mortality.
Project description:Inflammaging, the chronic, progressive proinflammatory state associated with aging, has been associated with multiple negative health outcomes in humans. The pathophysiology of inflammaging is complex; however, it is often characterized by high serum concentrations of inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and C-reactive protein (CRP). Few studies have evaluated the effects of age on inflammatory cytokines in companion dogs, and most of these studies included dogs of a single breed. In this cross-sectional study, we measured multiple circulating inflammatory markers and hematological parameters in banked serum samples from 47 healthy companion dogs of various breeds enrolled in the Dog Aging Project. Using univariate linear models, we investigated the association of each of these markers with age, sex, body weight, and body condition score (BCS), a measure of obesity in the dog. Serum IL-6, IL-8, and TNF-α concentrations were all positively associated with age. Lymphocyte count was negatively associated with age. Platelet count had a negative association with body weight. IL-2, albumin, cholesterol, triglyceride, bilirubin, S100A12, and NMH concentrations were not associated with age, weight, BCS, or sex after adjustment for multiple comparisons. Our findings replicate previous findings in humans, including increases in IL-6 and TNF-α with age, giving more evidence to the strength of the companion dog as a model for human aging.
Project description:Disturbances in bone morphogenetic protein (BMP) signalling contribute to onset and development of a number of rare genetic diseases, including Fibrodysplasia ossificans progressiva (FOP), Pulmonary arterial hypertension (PAH), and Hereditary haemorrhagic telangiectasia (HHT). After decades of animal research to build a solid foundation in understanding the underlying molecular mechanisms, the progressive implementation of iPSC-based patient-derived models will improve drug development by addressing drug efficacy, specificity, and toxicity in a complex humanized environment. We will review the current state of literature on iPSC-derived model systems in this field, with special emphasis on the access to patient source material and the complications that may come with it. Given the essential role of BMPs during embryonic development and stem cell differentiation, gain- or loss-of-function mutations in the BMP signalling pathway may compromise iPSC generation, maintenance, and differentiation procedures. This review highlights the need for careful optimization of the protocols used. Finally, we will discuss recent developments towards complex in vitro culture models aiming to resemble specific tissue microenvironments with multi-faceted cellular inputs, such as cell mechanics and ECM together with organoids, organ-on-chip, and microfluidic technologies.
Project description:The increasing trend of dog ownership is often linked to its perceived benefits for human physical and mental well-being. However, the psychological and practical demands of caring for a dog can significantly impact the owner's quality of life and the long-term success of the dog-owner relationship. This study aimed to provide a comprehensive overview of both the advantages and disadvantages of dog ownership, as perceived by a convenience sample of Hungarian dog owners (N = 246), who were assumed to be generally satisfied with their dogs. The study employed both quantitative (a Cost/Benefit scale consisting of 33 neutrally-phrased statements rated on a seven-point scale, from - 3 to + 3) and qualitative methods (two open-ended questions). Quantitative results showed that owners rated the short lifespan of dogs as the most negative aspect, while the belief that dogs brighten their lives was rated most positively. On average, positive statements were rated significantly higher (2.06) than negative ones (-0.66), supporting the prediction from social exchange theory that dog owners in a voluntary sample tend to perceive more advantages than disadvantages in dog ownership. Qualitative findings revealed six 'benefit' and three 'cost' themes. 61% of owners considered the meaningful relationship with their dog as the greatest benefit, frequently mentioning the dog's constant presence, love, and support. Additionally, 15% highlighted the relationship with another species and the dog's intrinsic qualities, indicating the biophilia effect of dog ownership. Regarding the costs, 95% of respondents identified financial, particularly health-related expenses, as the most significant drawback, and only 4-5% mentioned emotional or practical burdens. In the quantitative data, principal component analysis revealed three core components of the dog ownership experience: (1) emotional, physical, and social benefits, (2) negative emotions and practical challenges, and (3) time and emotional commitment. Overall, the results suggest clear costs and benefits, though some aspects, such as daily care, holiday arrangements, and training, were seen as both beneficial and disadvantageous, depending on the owner. Even within a convenience sample, the diversity in dog and owner characteristics was sufficient to explain why certain facets of dog ownership are experienced differently.
Project description:Chronic diseases (CD) are generating a dramatic societal burden worldwide that is expected to persist over the next decades. The challenges posed by the epidemics of CD have triggered a novel health paradigm with major consequences on the traditional concept of disease and with a profound impact on key aspects of healthcare systems. We hypothesized that the development of a systems approach to understand CD together with the generation of an ecosystem to transfer the acquired knowledge into the novel healthcare scenario may contribute to a cost-effective enhancement of health outcomes. To this end, we designed the Synergy-COPD project wherein the heterogeneity of chronic obstructive pulmonary disease (COPD) was addressed as a use case representative of CD. The current manuscript describes main features of the project design and the strategies put in place for its development, as well the expected outcomes during the project life-span. Moreover, the manuscript serves as introductory and unifying chapter of the different papers associated to the Supplement describing the characteristics, tools and the objectives of Synergy-COPD.
Project description:Research in chemoprevention has undergone a shift in emphasis for pragmatic reasons from large, phase III randomized studies to earlier phase studies focused on safety, mechanisms, and utilization of surrogate endpoints such as biomarkers instead of cancer incidence. This transition permits trials to be conducted in smaller populations and at substantially reduced costs while still yielding valuable information. This article will summarize some of the current chemoprevention challenges and the justification for the use of animal models to facilitate identification and testing of chemopreventive agents as illustrated though four inherited cancer syndromes. Preclinical models of inherited cancer syndromes serve as prototypical systems in which chemopreventive agents can be developed for ultimate application to both the sporadic and inherited cancer settings.
Project description:The companion dog is one of the most phenotypically diverse species. Variability between breeds extends not only to morphology and aspects of behaviour, but also to longevity. Despite this fact, little research has been devoted to assessing variation in life expectancy between breeds or evaluating the potential for phylogenetic characterisation of longevity. Using a dataset of 584,734 unique dogs located within the UK, including 284,734 deceased, we present variation in longevity estimates within the following: parental lineage (purebred = 1 breed, crossbred ≥ 2 breeds), breed (n = 155), body size (large, medium, small), sex (male, female) and cephalic index (brachycephalic, mesocephalic, dolichocephalic). Survival estimates were then partitioned amongst phylogenetic clades: providing evidence that canine evolutionary history (via domestication and associated artificial selection) is associated with breed lifespan. This information provides evidence to inform discussions regarding pedigree health, whilst helping current/prospective owners, breeders, policy makers, funding bodies and welfare organisations improve decision making regarding canine welfare.
Project description:Despite availability of video content marketed for dog (Canis familiaris) entertainment, there is little information on dog behaviors when viewing content, nor describing which content is engaging. The aims of this study were to define demographics of dogs that engage with screens, owner observed behaviors, and perceived content interest. A digital survey was distributed to dog owners (03/2022-03/2023). We collected demographics, home environment, owner-rated behaviors, content interest, and interest in 4 presented videos. We compared the representation of dogs from different purebred dog groups (categorized by job/purpose by the American Kennel Club) with the estimated general purebred dog population. Most respondents (total n=1,246) lived in the USA (89%). Median age was 4 years, 54% were purebred, 51% were female. Most (86%, n=1,077) stated their dog watched screen content. Excitement behaviors were often described: 78% of dogs approached the screen, 76% vocalized. Many owners played videos for their dogs when left alone. Dogs most frequently engaged with animal content; dogs were the most popular animal. Age and visual status influenced the frequency of perceived interaction; age and breed influenced content interest. Within purebred dogs that were stated to watch content, there was a relative over-representation of "sporting" and "herding"-type breeds. A dog's age, visual status, and breed type may influence their interest in video content at home. Because many owners reported excitement in their dogs in reaction to screen content, owners may wish to determine whether video content would be suitable for use when their dogs are left alone.
Project description:Advances in both imaging techniques and genetics have led to the recognition of a wide variety of aortic anomalies that can be grouped under the term 'hereditary thoracic aortic diseases'. The present review aims to summarize this very heterogeneous population's clinical, genetic, and imaging characteristics and to discuss the implications of the diagnosis for clinical counselling (on sports activity or pregnancy), medical therapies and surgical management.
Project description:Owner behaviour change may be the most promising avenue to improve dog welfare. As such, understanding potential drivers of owner behaviour is critical to developing effective intervention programs. Here we examine in depth the concept of "duty of care" as a motivator of owner behaviour. Using a mixed methods approach, this study aimed to better understand the potential dimensions of duty of care, their interrelationships, and develop psychometrically valid tools to measure them in companion dog owners. This was achieved through a multi-stage process including a critical literature review, qualitative interviews (n = 13), and an online survey (n = 538). Using Schwartz's Norm Activation Model as a framework, we have developed a 30 item scale with 5 subscales; duty beliefs, problem awareness, awareness of impact, efficacy, and ascription of responsibility. These unique subscales demonstrate good internal consistency and construct validity. In addition to developing a measurement tool, this process has provided important insights into the nature of duty of care in companion dog owners, creating several avenues for future inquiry. One such finding was that many dog welfare problems may not be the result of lacking duty beliefs, but rather weaknesses in other "activation" factors such as problem awareness or ascription of responsibility. Further work is now required to understand the predictive validity of the scale and the relative influence of its different dimensions on owner behaviour and dog welfare outcomes. This will facilitate the identification of appropriate targets for intervention programs aimed at improving owner behaviour and consequently, dog welfare.