Pathology of Genetically Engineered and Other Mutant Mice. Группа авторов

are used. For example, some use a substrain where the Crb1^rd8 allele causing a retinal phenotype in C57BL/6N mice was corrected using TALEN‐mediated homology‐directed repair [48]. This website provides deep summaries of the data by gene, together with primary data that is also accessible through the IMPC API web services. At the time of writing, 6440 knockouts have been phenotyped for more than 600 parameters in embryonic and adult life. A schematic of the phenotyping pipeline is shown in Figure 2.3.

Large numbers of radiographs and histopathology images are available on IMPC together with embryo images using different modes of imaging. Histopathology images are available on https://www.mousephenotype.org/data/landing_pages/histopath for 580 genes and, where changes were diagnosed, use the combination of mouse pathology ontology (MPATH) and mouse anatomy ontology (MA) ontology terms as used in Pathbase (Figure 2.4). Embryos, as part of the embryonic lethality program, are visualized using OPT, micro CT, and whole mounts, including LacZ expression reporters. Volumetric data are available from the micro CT and images through the dedicated embryo viewer (https://www.mousephenotype.org/data/embryo_imaging). Radiographs were taken at week 14 and a standard set of orientations and organs displayed (see https://www.mousephenotype.org/impress/ProcedureInfo?action=list&procID=556).

      The website is set up such that IMPC data can be used in a variety of ways, such as to investigate basic biology mechanisms that can lead to new therapeutic targets or to narrow down a suspected list of genes in patients. As with the Lexicon studies, the IMPC has and continues to make discoveries related to a wide variety of diseases [50–53].

      MUTAGENETIX (https://mutagenetix.utsouthwestern.edu)

MUTAGENETIX is a database of immunological phenotypes of single gene mouse mutants produced by ENU mutagenesis. It currently contains data generated by the Beutler Lab at the University of Texas Southwestern Medical Center and the Goodnow Lab at the Australian National University and provides access to strains maintained at these centers. The immunological data are very rich and the site contains information about protocols and breeding procedures that are very valuable. Note that incidental, nonimmunological phenotypes are also described for some mutations, such as growth, skin, and endocrine phenotypes. The site is updated regularly (https://mutagenetix.utsouthwestern.edu) [54, 55].

Figure 2.3 IMPC phenotyping pipelines for adult mice (17 weeks) and embryos.

Figure 2.4 The histopathology browser for the IMPC database. Data can be searched for by gene and, where phenotyping of the strain has been completed, users can find data from individual mice, with zygosity of the knockout and in many cases, a diagnostic assessment with lesion and anatomical location derived from the MPATH and MA ontologies and used combinatorially. There are also estimates of severity and microanatomical qualifiers. The use of the ontologies in this way is described in Elmore et al. [49]. Selected hematoxylin and eosin stained images are available.

Background Strain Comparison Studies

      Mouse Phenome Database (https://phenome.jax.org)

      The Mouse Phenome Database (MPD) was originally envisioned as a site to host data on comparative studies that utilized multiple inbred strains. It provided a repository for the primary data. As the site evolved, the data could be manipulated to generate a variety of tables to define quantitative differences for specific phenotypes between strains. Today, the site has been refined enabling integration of genomic and phenomic data by providing access to primary experimental data, well‐documented data collection protocols, and a variety of tools to analyze these datasets. Investigators worldwide provided the data on this site which represent a broad scope of disease‐related characteristics in the inbred mouse strains to variations in behavior, morphological, and physiological differences in naive mice and those exposed to drugs, environmental agents, or other manipulations [56].

Mouse Pathology Image (Histopathology) Resources

      Pathbase, the European Mouse Pathology Database (http://www.pathbase.net)

      Pathbase is a community resource for images of all types of lesions and normal tissues from laboratory mice [57, 58]. Pathologists from all over the world, not just Europe, provide photomicrographs of lesions diagnosed in laboratory mice. While initially the goal was to illustrate lesions in genetically engineered mice, this website has evolved to include all types of mouse diseases as well as normal tissues including large collections of images from aged inbred mouse strain studies [33]. These data are curated in an ontology built around the Mouse Anatomy (MA) [59] and Mouse Pathology (MPATH) [60] ontologies, with more refinement for selected organs, such as skin [61]. This enables rapid retrieval of histologic images. In fact, if one integrates this into a diagnostic database, one can use the diagnostic term to go to Pathbase to look up the definition of the term and then access images of lesions with that diagnosis provided by numerous pathologists from around the world, something called the “virtual second opinion” [62]. Integration of the Mouse Anatomy and Pathology Ontologies into diagnostic laboratory software sets up a controlled vocabulary that enables consistent data searches to enable high‐level computational analysis of the dataset [62, 63].

      National Toxicology Program Neoplastic Lesion Atlas (https://ntp.niehs.nih.gov/nnl/index.htm)

      The National Toxicology Program Atlas of Nonneoplastic Lesions in Rats and Mice is a publicly accessible resource built around the goal of identifying potential human carcinogens in rodent bioassays. Nonneoplastic diseases are also a major cause of morbidity and mortality in humans. This atlas provides diagnostic guidelines for histologic lesions in both rats and mice. This was built around an effort to maintain consistency with lesion terminology through the creation of the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) monograph series [64, 65] and classification systems in textbooks [66, 67]. A web resource for INHAND can be found on https://www.toxpath.org/inhand.asp.

      The database is organized by major organ systems (alimentary, cardiovascular, endocrine, hematopoietic, hepatobiliary, immune, integumentary, musculoskeletal, nervous, reproductive [female and male], respiratory, special senses, and urinary) and within each category are a limited number of examples of lesions with a representative image. This is useful for getting started to gain a basic understanding of lesions, terms, and definitions. Unfortunately, while aimed at standardizing toxicology diagnoses, it does not embrace the complexity of human disease making it relatively superficial and not helpful to define a mouse model for a human disease.

      Noah's Arkive, Charles Louis Davis, and Samuel Wesley Thompson Foundation for the Advancement of Veterinary and Comparative Pathology (http://noahsarkive.cldavis.org/cgi‐bin/show_image_info_page.cgi)