Animal models of alphavirus infection and human disease.

The International Society for Biological and Environmental Repositories Presents Abstracts from Its Annual Meeting

The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases.

Platelet adhesion in the microcirculation is being reported and studied in a growing number of animal models of human disease. The adhesion molecules utilized by platelets to attach to the walls of microscopic blood vessels have been defined in most model systems, with P-selectin-PSGL-1, GPIIb/IIIa-fibrinogen-ICAM-1, and vWF-GPIba interactions serving as major adhesion pathways. The binding of platelets to adherent leukocytes appears to contribute significantly to the platelet-vessel wall interactions elicited in many models of disease. Shear forces generated by the movement of blood through the microcirculation exert an important influence on platelet adhesion. Physiologic regulation of platelet adhesion is mediated by both nitric oxide and superoxide, with the former inhibiting and the latter promoting platelet adhesion. The interactions between platelets and the walls of microscopic blood vessels appear to have important implications in the initiation and/or progression of tissue injury associated with different experimental models of human disease.

Continued population growth and clear evidence of climate change are placing unprecedented strain on food production and health care systems worldwide. Agricultural production goals that highlight environmental sustainability are at the forefront of social dialog, with animal agriculture routinely targeted for inefficiencies, welfare concerns and impact on climate. Genomic selection has transformed animal production and the rate of genetic gain in each generation continues to increase. Nonetheless, it is apparent that the rate of production gains will fall short of the necessary goals of increased efficiency and adaptation to the changing environment. Genetic engineering may have an important role in enhancing livestock production as well as providing new models for research in human health. The CRISPR/Cas and related systems for targeted gene editing has revolutionized livestock genetic engineering by increasing the rate of targeted mutation, thus drastically reducing the cost of producing founder animals with the desired trait. Intentional insertion of well-known mutations into genes such as myostatin have been shown to impart the expected increase in meat production, but have also resulted in undesirable associated traits affecting fertility, marbling and the skeleton. Thus, the approach to increasing meat production may require nuances such as promotor targeting and multiple gene targeting to obtain the desired production characteristics. Efforts to increase disease resistance could have dramatic impacts on animal welfare and production rates, potentially saving millions of animals from morbidity and mortality. However, confronting a single disease with each genetic alteration will be costly and inefficient. Considerations on how broad scale disease resistance could be achieved through genetic engineering will be instrumental in developing livestock with advantages to avoid infection and/or transmission of multiple pathogens. Gene editing also allows correction of mutations that arise in livestock through natural mechanisms while under intense genomic selection for increased production. Removing disease causing mutations in otherwise high value livestock will allow continued production from these lines without concern for inheriting the causative mutation. The same process can be utilized to insert genetic mutations known to phenocopy human conditions providing valuable large animal models of human genetic disease. Increased milk, meat, or eggs per animal unit will sustainably improve high quality, nutrient dense food production while large animal models of human disease will provide a more translational biomedical model for accelerated development of drugs and treatments. These goals are achievable, but require continued investment in innovation, clear regulatory framework for commercialization, education, and public engagement to ensure success.

Gender and human chronic renal disease

Investigations by using animal models offer a useful tool to study the pathogenesis and the cure of several intractable human diseases. The laboratory animal science in this field was established about 23 years ago in Japan. Since 1973, the Japanese association of laboratory animal science started to play an active part in exchanging information among investigators with regard to the finding of new genetic mutants. The association then organized a working group in 1987, to inquire into the distribution of animal models all over the country and to grasp the status of their maintenance in as many experimental animal stations and laboratories as possible.The other research groups sponsored by the Ministry of Education, and Health and Welfare began in 1976 and in 1979, respectively, to examine the same subjects. They investigated the clinical and pathological changes in every affected animals in greater detail than before to determine their degree of resemblance to human diseases.On the other hand, the research team on human muscular dystrophy had been organized by the Ministry of Health and Welfare in 1968, and had begun to study independently of the others. A group of investigators, who were studying on the development and improvement of the new mutants for muscular dystrophy, formed a part of this research team for 10 years. They separated from the original research team in 1978 and organized a new team. The well-known three animal models for human muscular dystrophy; mouse, chicken, and hamster were introduced from other countries and maintained by this team. Their genetic modes were analyzed, and the clinical and pathological changes were studied from all angles.This paper will introduce the animal models for human muscular and neurological diseases which have been studied intensively and are expected to be useful for the future in Japan.

In this eighteenth (2016) Annual Review Issue of The Journal of Pathology, we present a collection of 19 invited review articles that cover different aspects of cellular and animal models of disease. These include genetically-engineered models, chemically-induced models, naturally-occurring models, and combinations thereof, with the focus on recent methodological and conceptual developments across a wide range of human diseases.

Cloned ferrets produced by somatic cell nuclear transfer

Chapter 10 - Animal Models for Chikungunya Virus and Zika Virus

To accurately analyze the function of transgene(s) of interest in transgenic mice, and to generate credible transgenic animal models for multifarious human diseases to precisely mimic human disease states, it is critical to tightly regulate gene expression in the animals in a conditional manner. The ability to turn gene expression on or off in the restricted cells or tissues at specific time permits unprecedented flexibility in dissecting gene functions in health and disease. Pioneering studies in conditional transgene expression have brought about the development of a wide variety of controlled gene expression systems, which meet this criterion. Among them, the tetracycline-controlled expression systems (e.g. Tet-off system and Tet-on system) have been used extensively in vitro and in vivo. In recent years, some strategies derived from tetracycline-inducible system alone, as well as the combined use of Tet-based systems and Cre/lox P switching gene expression system, have been newly developed to allow more flexibility for exploring gene functions in health and disease, and produce credible transgenic animal models for various human diseases. In this review these newly developed strategies are discussed.

Models that buzz, squeak, ribbit and oink: using a variety of species to study cardiovascular disease

This preclinical study in the gnotobiotic (Gn) pig model of human rotavirus (HRV) infection and disease evaluates the effect of probiotic Lactobacillus rhamnosus GG (LGG) as a mucosal adjuvant on the immunogenicity and cross-protective efficacy of the Lanzhou live oral trivalent (G2, G3, G4) vaccine (TLV, aka LLR3). Gn pigs were immunized with three doses of TLV with or without concurrent administration of nine doses of LGG around the time of the first dose of the TLV vaccination, and were challenged orally with the virulent heterotypic Wa G1P[8] HRV. Three doses of TLV were highly immunogenic and conferred partial protection against the heterotypic HRV infection. LGG significantly enhanced the intestinal and systemic immune responses and improved the effectiveness of protection against the heterotypic HRV challenge-induced diarrhea and virus shedding. In conclusion, we demonstrated the immune-stimulating effects of probiotic LGG as a vaccine adjuvant and generated detailed knowledge regarding the cross-reactive and type-specific antibody and effector B and T cell immune responses induced by the TLV. Due to the low cost, ease of distribution and administration, and favorable safety profiles, LGG as an adjuvant has the potential to play a critical role in improving rotavirus vaccine efficacy and making the vaccines more cost-effective.

The burden of cardiovascular and metabolic diseases worldwide is staggering. The emergence of systems approaches in biology promises new therapies, faster and cheaper diagnostics, and personalized medicine. However, a profound understanding of pathogenic mechanisms at the cellular and molecular levels remains a fundamental requirement for discovery and therapeutics. Animal models of human disease are cornerstones of drug discovery as they allow identification of novel pharmacological targets by linking gene function with pathogenesis. The zebrafish model has been used for decades to study development and pathophysiology. More than ever, the specific strengths of the zebrafish model make it a prime partner in an age of discovery transformed by big-data approaches to genomics and disease. Zebrafish share a largely conserved physiology and anatomy with mammals. They allow a wide range of genetic manipulations, including the latest genome engineering approaches. They can be bred and studied with remarkable speed, enabling a range of large-scale phenotypic screens. Finally, zebrafish demonstrate an impressive regenerative capacity scientists hope to unlock in humans. Here, we provide a comprehensive guide on applications of zebrafish to investigate cardiovascular and metabolic diseases. We delineate advantages and limitations of zebrafish models of human disease and summarize their most significant contributions to understanding disease progression to date.

The field of stem cell biology and regenerative medicine is rapidly moving toward translation to clinical practice, and in doing so has become more dependent on animal donors and hosts for generating cellular reagents and assaying their potential therapeutic efficacy in models of human disease. Animal models of cardiovascular disease have proved critically important for the discovery of pathophysiological mechanisms and for the advancement of diagnosis and therapy. They offer a number of advantages; principally the availability of adequate healthy controls and the absence of confounding factors such as marked differences in age, concomitant pathologies, and pharmacological treatments. Over the past 30 years, investigators have developed numerous small and large animal models to study heart failure (HF). However, to translate discoveries from basic science into medical applications, research in large animal models becomes a necessary step. Intracoronary microembolizations-induced HF in dogs is an excellent large animal model of congestive HF for the assessment of pharmacological drugs, medical devices, and stem cells.

Asparaginyl endopeptidase, or legumain, is a lysosomal cysteine protease that was originally identified in plants and later found to be involved in antigen presentation in higher eukaryotes. Legumain is also up-regulated in a number of human cancers, and recent studies suggest that it may play important functional roles in the process of tumorigenesis. However, detailed functional studies in relevant animal models of human disease have been hindered by the lack of suitably selective small molecule inhibitors and imaging reagents. Here we present the design, optimization, and in vivo application of fluorescently labeled activity-based probes (ABPs) for legumain. We demonstrate that optimized aza-peptidyl Asn epoxides are highly selective and potent inhibitors that can be readily converted into near-infrared fluorophore-labeled ABPs for whole body, noninvasive imaging applications. We show that these probes specifically label legumain in various normal tissues as well as in solid tumors when applied in vivo. Interestingly, addition of cell-penetrating peptides to the probes enhanced cellular uptake but resulted in increased cross-reactivity toward other lysosomal proteases as the result of their accumulation in lysosomes. Overall, we find that aza-peptidyl Asn ABPs are valuable new tools for the future study of legumain function in more complex models of human disease.