Pathology Principles and Practices for Analysis of Animal Models

Abstract Over 60% of NIH extramural funding involves animal models, and approximately 80% to 90% of these are mouse models of human disease. It is critical to translational research that animal models are accurately characterized and validated as models of human disease. Pathology analysis, including histopathology, is essential to animal model studies by providing morphologic context to in vivo, molecular, and biochemical data; however, there are many considerations when incorporating pathology endpoints into an animal study. Mice, and in particular genetically modified models, present unique considerations because these modifications are affected by background strain genetics, husbandry, and experimental conditions. Comparative pathologists recognize normal pathobiology and unique phenotypes that animals, including genetically modified models, may present. Beyond pathology, comparative pathologists with research experience offer expertise in animal model development, experimental design, optimal specimen collection and handling, data interpretation, and reporting. Critical pathology considerations in the design and use of translational studies involving animals are discussed, with an emphasis on mouse models.

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Preclinical Testing of Radiopharmaceuticals for the Detection and Characterization of Osteomyelitis: Experiences from a Porcine Model

Molecules ◽

10.3390/molecules26144221 ◽

2021 ◽

Vol 26 (14) ◽

pp. 4221

Author(s):

Aage Kristian Olsen Alstrup ◽

Svend Borup Jensen ◽

Ole Lerberg Nielsen ◽

Lars Jødal ◽

Pia Afzelius

Keyword(s):

Animal Model ◽

Animal Models ◽

Porcine Model ◽

Animal Experiments ◽

Radioactive Tracers ◽

The Individual ◽

Selection Of

The development of new and better radioactive tracers capable of detecting and characterizing osteomyelitis is an ongoing process, mainly because available tracers lack selectivity towards osteomyelitis. An integrated part of developing new tracers is the performance of in vivo tests using appropriate animal models. The available animal models for osteomyelitis are also far from ideal. Therefore, developing improved animal osteomyelitis models is as important as developing new radioactive tracers. We recently published a review on radioactive tracers. In this review, we only present and discuss osteomyelitis models. Three ethical aspects (3R) are essential when exposing experimental animals to infections. Thus, we should perform experiments in vitro rather than in vivo (Replacement), use as few animals as possible (Reduction), and impose as little pain on the animal as possible (Refinement). The gain for humans should by far exceed the disadvantages for the individual experimental animal. To this end, the translational value of animal experiments is crucial. We therefore need a robust and well-characterized animal model to evaluate new osteomyelitis tracers to be sure that unpredicted variation in the animal model does not lead to a misinterpretation of the tracer behavior. In this review, we focus on how the development of radioactive tracers relies heavily on the selection of a reliable animal model, and we base the discussions on our own experience with a porcine model.

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Engineering, Generation and Preliminary Characterization of a Humanized Porcine Sickle Cell Disease Animal Model

10.1101/2020.09.15.291864 ◽

2020 ◽

Author(s):

Tobias M. Franks ◽

Sharie J. Haugabook ◽

Elizabeth A. Ottinger ◽

Meghan S. Vermillion ◽

Kevin M. Pawlik ◽

...

Keyword(s):

Animal Model ◽

Sickle Cell Disease ◽

Mouse Models ◽

Sickle Cell ◽

Cell Model ◽

Globin Genes ◽

Cell Disease ◽

Small Vessels

AbstractMouse models of sickle cell disease (SCD) that faithfully switch from fetal to adult hemoglobin (Hb) have been important research tools that accelerated advancement towards treatments and cures for SCD. Red blood cells (RBCs) in these animals sickled in vivo, occluded small vessels in many organs and resulted in severe anemia like in human patients. SCD mouse models have been valuable in advancing clinical translation of some therapeutics and providing a better understanding of the pathophysiology of SCD. However, mouse models vary greatly from humans in their anatomy and physiology and therefore have limited application for certain translational efforts to transition from the bench to bedside. These differences create the need for a higher order animal model to continue the advancement of efforts in not only understanding relevant underlying pathophysiology, but also the translational aspects necessary for the development of better therapeutics to treat or cure SCD. Here we describe the development of a humanized porcine sickle cell model that like the SCD mice, expresses human ɑ-, β− and γ-globin genes under the control of the respective endogenous porcine locus control regions (LCR). We also describe our initial characterization of the SCD pigs and plans to make this model available to the broader research community.

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Animal Models in Peritoneal Dialysis Research: A Need for Consensus

Peritoneal Dialysis International ◽

10.1177/089686080502500105 ◽

2005 ◽

Vol 25 (1) ◽

pp. 16-24 ◽

Cited By ~ 16

Author(s):

Siska Mortier ◽

Norbert H. Lameire ◽

An S. De Vriese

Keyword(s):

Animal Model ◽

Peritoneal Dialysis ◽

Animal Models ◽

Solute Transport ◽

Experimental Models ◽

Research Groups ◽

Experimental Animals ◽

Collective Effort ◽

Study Duration

The development of an adequate animal model for peritoneal research remains an object of concern. In vivo peritoneal dialysis (PD) research is hampered by the large variety of available models that make interpretation of results and comparison of studies very difficult. Species and strain of experimental animals, method of peritoneal access, study duration, measures of solute transport and ultrafiltration, and sampling for histology differ substantially among the various research groups. A collective effort to discuss the shortcomings and merits of the different experimental models may lead to a consensus on a standardized animal model of PD.

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In Vivo Models for Cholangiocarcinoma—What Can We Learn for Human Disease?

International Journal of Molecular Sciences ◽

10.3390/ijms21144993 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4993 ◽

Cited By ~ 1

Author(s):

Raphael Mohr ◽

Burcin Özdirik ◽

Jana Knorr ◽

Alexander Wree ◽

Münevver Demir ◽

...

Keyword(s):

Animal Models ◽

Human Disease ◽

Liver Tumors ◽

Tumor Biology ◽

Genetic Alterations ◽

In Vivo Models ◽

Primary Liver Tumors ◽

Stromal Microenvironment

Cholangiocarcinoma (CCA) comprises a heterogeneous group of primary liver tumors. They emerge from different hepatic (progenitor) cell populations, typically via sporadic mutations. Chronic biliary inflammation, as seen in primary sclerosing cholangitis (PSC), may trigger CCA development. Although several efforts were made in the last decade to better understand the complex processes of biliary carcinogenesis, it was only recently that new therapeutic advances have been achieved. Animal models are a crucial bridge between in vitro findings on molecular or genetic alterations, pathophysiological understanding, and new therapeutic strategies for the clinic. Nevertheless, it is inherently difficult to recapitulate simultaneously the stromal microenvironment (e.g., immune-competent cells, cholestasis, inflammation, PSC-like changes, fibrosis) and the tumor biology (e.g., mutational burden, local growth, and metastatic spread) in an animal model, so that it would reflect the full clinical reality of CCA. In this review, we highlight available data on animal models for CCA. We discuss if and how these models reflect human disease and whether they can serve as a tool for understanding the pathogenesis, or for predicting a treatment response in patients. In addition, open issues for future developments will be discussed.

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Preclinical Molecular Imaging for Precision Medicine in Breast Cancer Mouse Models

Contrast Media & Molecular Imaging ◽

10.1155/2019/8946729 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 4

Author(s):

M. F. Fiordelisi ◽

L. Auletta ◽

L. Meomartino ◽

L. Basso ◽

G. Fatone ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Imaging ◽

Animal Models ◽

Early Detection ◽

Mouse Models ◽

Molecular Mechanisms ◽

Clinical Medicine ◽

High Sensitivity ◽

Positron Emission

Precision and personalized medicine is gaining importance in modern clinical medicine, as it aims to improve diagnostic precision and to reduce consequent therapeutic failures. In this regard, prior to use in human trials, animal models can help evaluate novel imaging approaches and therapeutic strategies and can help discover new biomarkers. Breast cancer is the most common malignancy in women worldwide, accounting for 25% of cases of all cancers and is responsible for approximately 500,000 deaths per year. Thus, it is important to identify accurate biomarkers for precise stratification of affected patients and for early detection of responsiveness to the selected therapeutic protocol. This review aims to summarize the latest advancements in preclinical molecular imaging in breast cancer mouse models. Positron emission tomography (PET) imaging remains one of the most common preclinical techniques used to evaluate biomarker expression in vivo, whereas magnetic resonance imaging (MRI), particularly diffusion-weighted (DW) sequences, has been demonstrated as capable of distinguishing responders from nonresponders for both conventional and innovative chemo- and immune-therapies with high sensitivity and in a noninvasive manner. The ability to customize therapies is desirable, as this will enable early detection of diseases and tailoring of treatments to individual patient profiles. Animal models remain irreplaceable in the effort to understand the molecular mechanisms and patterns of oncologic diseases.

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ANIMAL MODELS FOR THE STUDY OF LEISHMANIASIS IMMUNOLOGY

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652014000100001 ◽

2014 ◽

Vol 56 (1) ◽

pp. 1-11 ◽

Cited By ~ 61

Author(s):

Elsy Nalleli Loria-Cervera ◽

Fernando Jose Andrade-Narvaez

Keyword(s):

Animal Models ◽

Human Disease ◽

Public Health Problem ◽

Leishmania Species ◽

Experimental Models ◽

Sand Fly ◽

Leishmania Infection ◽

Major Public Health Problem ◽

Wild Rodents ◽

Experimental Conditions

Leishmaniasis remains a major public health problem worldwide and is classified as Category I by the TDR/WHO, mainly due to the absence of control. Many experimental models like rodents, dogs and monkeys have been developed, each with specific features, in order to characterize the immune response to Leishmania species, but none reproduces the pathology observed in human disease. Conflicting data may arise in part because different parasite strains or species are being examined, different tissue targets (mice footpad, ear, or base of tail) are being infected, and different numbers (“low” 1×102 and “high” 1×106) of metacyclic promastigotes have been inoculated. Recently, new approaches have been proposed to provide more meaningful data regarding the host response and pathogenesis that parallels human disease. The use of sand fly saliva and low numbers of parasites in experimental infections has led to mimic natural transmission and find new molecules and immune mechanisms which should be considered when designing vaccines and control strategies. Moreover, the use of wild rodents as experimental models has been proposed as a good alternative for studying the host-pathogen relationships and for testing candidate vaccines. To date, using natural reservoirs to study Leishmania infection has been challenging because immunologic reagents for use in wild rodents are lacking. This review discusses the principal immunological findings against Leishmania infection in different animal models highlighting the importance of using experimental conditions similar to natural transmission and reservoir species as experimental models to study the immunopathology of the disease.

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From Mouse to Man

Annual Review of Nursing Research ◽

10.1891/0739-6686.29.99 ◽

2011 ◽

Vol 29 (1) ◽

pp. 99-112

Author(s):

Cynthia L. Renn ◽

Susan G. Dorsey

Keyword(s):

Animal Model ◽

Animal Models ◽

Human Disease ◽

Research Process ◽

Critical Component ◽

Exponential Expansion ◽

Genomics Research ◽

The Common ◽

Genetics And Genomics ◽

Careful Thought

Animal models are a critical component of biomedical and biobehavioral research and have contributed to the exponential expansion of our understanding of human disease. Now, as we move onward into the era of genetics and genomics research, the importance of animal models to the research process will become even more acute as we explore the significance of genetic differences that are found in the presence and absence of disease. The decision to use an animal model is not one that can be taken lightly; but, rather, requires careful thought and consideration. In this review, we will address (a) why we should consider using animal models, (b) several caveats that are associated with using animals for research, and (c) some of the common genetic tools that are used in animal research.

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Animal Models for imaging

Disease Markers ◽

10.1155/2002/760473 ◽

2002 ◽

Vol 18 (5-6) ◽

pp. 365-374 ◽

Cited By ~ 10

Author(s):

Barbara Y. Croft

Keyword(s):

Animal Models ◽

Human Disease ◽

Imaging Techniques ◽

Primary Model ◽

The Future ◽

Research Choices

Animal models can be used in the study of disease. This chapter discusses imaging animal models to elucidate the process of human disease. The mouse is used as the primary model. Though this choice simplifies many research choices, it necessitates compromises forin vivoimaging. In the future, we can expect improvements in both animal models and imaging techniques.

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Saturation mutagenesis defines novel mouse models of severe spine deformity

Disease Models & Mechanisms ◽

10.1242/dmm.048901 ◽

2021 ◽

Author(s):

Jonathan J Rios ◽

Kristin Denton ◽

Hao Yu ◽

Kandamurugu Manickam ◽

Shannon Garner ◽

...

Keyword(s):

Mouse Models ◽

Human Disease ◽

Spinal Column ◽

Saturation Mutagenesis ◽

Recessive Mutation ◽

Spine Deformity ◽

Skeletal Disease ◽

Genetic Mouse Models

Embryonic formation and patterning of the vertebrate spinal column requires coordination of many molecular cues. After birth, the integrity of the spine is impacted by developmental abnormalities of the skeletal, muscular, and nervous systems, which may result in deformities such as kyphosis and scoliosis. We sought to identify novel genetic mouse models of severe spine deformity by implementing in vivo skeletal radiography as part of a high-throughput saturation mutagenesis screen. We report selected examples of genetic mouse models following radiographic screening of 54,497 mice from 1,275 pedigrees. An estimated 30.44% of autosomal genes harbored predicted damaging alleles examined twice or more in the homozygous state. Of the 1,275 pedigrees screened, 7.4% presented with severe spine deformity developing in multiple mice, and of these, meiotic mapping implicated ENU alleles in 21% of pedigrees. Our study provides proof-of-concept that saturation mutagenesis is capable of discovering novel mouse models of human disease, including conditions with skeletal, neural, and neuromuscular pathologies. Furthermore, we report a mouse model of skeletal disease, including severe spine deformity, caused by recessive mutation in Scube3. By integrating results with a human clinical exome database, we identified a patient with undiagnosed skeletal disease who harbored recessive mutations in SCUBE3, and we demonstrated that disease-associated mutations are associated with reduced trans-activation of Smad signaling in vitro. All radiographic results and mouse models are made publicly available through the Mutagenetix online database with the goal of advancing understanding of spine development and discovering novel mouse models of human disease.

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