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Phenotyping Rat Cancer Models

In order to better understand both normal and abnormal situations in organisms or in various tissues, a number of techniques are used to assess the state, content, or responses to stimuli or treatments in rats. Phenotyping refers to the strategies to understand the biological consequences of genomic variation, alteration, or outcomes that may or may not be related to DNA content or features in cells.  For example, stress on an animal could cause alterations in blood pressure and circulating hormones, elicit changes in gene expression in various tissues, affect food intake, and alter many more aspects of biology. These reactions can be measured and compared with control animals or other strains to find informative leads about underlying biological mechanisms.  Depending on the focus of the research, any number of protocols and tools can be used to assess the biological state. The techniques and directions will be highly dependent on the research topic, tissue, and conditions involved. Here we provide a framework for finding helpful phenotyping resources and strategies that may be useful. 

Phenotyping strategies will vary depending on the stage of the animal’s life under investigation as well.  When creating models, prenatal phenotypes can be a complicating issue. If prenatal phenotypes are lethal, there will be no animals to evaluate. If phenotypes are developmentally damaging, it may be challenging to determine when the defect initiates.  Postnatal phenotyping will employ different methods depending on the age and sex of the animals.  Many of the same issues in phenotyping across the lifespan will be shared with mice, and strategies and projects that addressed this for mice may also offer useful directions.

For additional details on assessing phenotypes of rats, you may explore texts such as The Laboratory Rat for reference data. Additional guidance may be obtained by scrutinizing protocols from phenotyping projects. The large National Toxicology Project (NTP) has generated extensive data on phenotypes and pathologies, many of them involving cancer.  The National BioResource Project in Japan is generating and collecting data as part of the Rat Phenome Project. The PhysGen effort provided more of this type of data as well, and developed a number of protocols. The RGD Phenotypes and Models Portal offers searchable access to phenotype data.  A standardized phenotyping ontology has been developed to describe the observations, and enables cross-species comparisons. Searching RGD data specifically for cancer phenotypes provides access to data and literature that may offer utility, and for a focus specifically on mammary cancer the Disease portal may be searched. The Ratmine database offers an entry point specific for mammalian phenotypes.

Physical phenotyping and imaging

Traditional phenotyping of animals has relied on measurements of various features of the body, body functions, tissue structure and composition, and responses such as hearing, vision, or behavior.  Many tools and strategies for investigating physiology, metabolism, pathology, and behavior of rats are in wide use, and repositories for rat research can provide access to extensive information on phenotypes.  Tissue histology methods have long been used to examine the structure and organization of tissues in normal and pathological situations. In some cases tissue staining with dyes and chemicals visible with light microscopy are employed.  Increasingly, less invasive methods for visualizing cells, tissues, and whole body systems are becoming available for small animals.  Special dyes and imaging methods are advancing and refining the opportunities for these types of investigations.

Molecular phenotyping

Performing molecular phenotyping to assess the gene transcripts, protein biomarkers and protein modifications that may be observed in normal tissues, tumors, and treatment settings is also becoming increasingly refined and may be used in many species.  Bioinformatics support for assessing the results continue to develop as well. Detection of changes in gene expression patterns at the mRNA or protein level can elucidate patterns of genes that are up-regulated or down-regulated and provide informative diagnostic signatures. PCR, array technologies and next-generation sequencing strategies may be used for this on RNA.  Various protein biomarkers are used as diagnostic indicators for cancerous changes, and can be detected via a range of mass-spectrometry technology, immunological detection methods, or using fluorescently-tagged proteins in mice.  Detection of protein modifications such as phosphorylation or dephosphorylation states can provide indications of biological activity that lead to clues about pathways involved in tumorigenesis. These types of investigations can be genome-wide, or can target specific pathways of interest.