Victoria E Kennedy

The Jackson Laboratory, BHB, Maine, United States

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Publications (14)59.94 Total impact

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    ABSTRACT: Technology now exists for rapid screening of mutated laboratory mice to identify phenotypes associated with specific genetic mutations. Large repositories exist for spontaneous mutants and those induced by chemical mutagenesis, many of which have never been fully studied or comprehensively evaluated. To supplement these resources, a variety of techniques have been consolidated in an international effort to create mutations in all known protein coding genes in the mouse. With targeted embryonic stem cell lines now available for almost all protein coding genes and more recently CRISPR/Cas9 technology, large-scale efforts are underway to create further novel mutant mouse strains and to characterize their phenotypes. However, accurate diagnosis of skin, hair, and nail diseases still relies on careful gross and histological analysis, and while not automated to the level of the physiological phenotyping, histopathology still provides the most direct and accurate diagnosis and correlation with human diseases. As a result of these efforts, many new mouse dermatological disease models are being characterized and developed.
    No preview · Article · Nov 2015 · Journal of Investigative Dermatology Symposium Proceedings
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    ABSTRACT: Fibro-osseous lesions in mice are progressive aging changes in which the bone marrow is replaced to various degrees by fibrovascular stroma and bony trabeculae in a wide variety of bones. The frequency and severity varied greatly among 28 different inbred mouse stains, predominantly affecting females, ranging from 0% for 10 strains to 100% for KK/HlJ and NZW/LacJ female mice. Few lesions were observed in male mice and for 23 of the strains, no lesions were observed in males for any of the cohorts. There were no significant correlations between strain-specific severities of fibro-osseous lesions and ovarian (r = 0.11; P = 0.57) or endometrial (r = 0.03; P = 0.89) cyst formation frequency or abnormalities in parathyroid glands. Frequency of fibro-osseous lesions was most strongly associated (P < 10(-6)) with genome variations on chromosome (Chr) 8 at 90.6 and 90.8 Mb (rs33108071, rs33500669; P = 5.0·10(-10), 1.3·10(-6)), Chr 15 at 23.6 and 23.8 Mb (rs32087871, rs45770368 ; P = 7.3·10(-7), 2.7·10(-6)), and Chr 19 at 33.2, 33.4, and 33.6 Mb (rs311004232, rs30524929, rs30448815; P = 2.8·10(-6), 2.8·10(-6), 2.8·10(-6)) in genome wide association studies (GWAS). The relatively large number of candidate genes identified in the GWAS analyses suggests that this may be an extremely complex polygenic disease. These results indicate that fibro-osseous lesions are surprisingly common in many inbred strains of laboratory mice as they age. While this presents little problem in most studies that utilize young animals, it may complicate aging studies, particularly those focused on bone.
    No preview · Article · Nov 2015 · Experimental and Molecular Pathology
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    ABSTRACT: An increased number of eosinophils in the esophagus are common in several esophageal and systemic diseases, and a prominent feature of eosinophilic esophagitis. Mouse models can provide insight into the mechanisms of eosinophil infiltration and their pathogenic role. SHARPIN-deficient cpdm mice develop a chronic proliferative dermatitis and an esophagitis characterized by epithelial hyperplasia and the accumulation of eosinophils in the serosa, submucosa, lamina propria and epithelium of the esophagus. We conducted a detailed investigation of the pathogenesis of the esophagitis by light microscopy, immunohistochemistry, and gene expression as the mice aged from 4 to 10weeks. The thickness of the esophageal epithelium and the number of eosinophils in the esophagus both increased with age. There were scattered apoptotic epithelial cells in mice at 6-10weeks of age that reacted with antibodies to activated caspase 3 and caspase 9. The expression of CCL11 (eotaxin-1), IL4, IL13 and TSLP was increased in cpdm mice compared with wild type (WT) mice, and there was no change in the expression of CCL24 (eotaxin-2), IL5 and IL33. The expression of chitinase-like 3 and 4 (YM1 and YM2) proteins, markers of type 2 inflammation, was greatly increased in cpdm mice, and this was replicated in vitro by incubation of WT esophagus in the presence of IL4 and IL13. Immunohistochemistry showed that these proteins were localized in esophageal epithelial cells. The severity of the esophagitis was not affected by crossing SHARPIN-deficient mice with lymphocyte-deficient Rag1 null mice indicating that the inflammation is independent of B and T lymphocytes. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Aug 2015 · Experimental and Molecular Pathology

  • No preview · Conference Paper · May 2015
  • Kathleen A Silva · Victoria E Kennedy · John P Sundberg
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    ABSTRACT: The skin and its adnexa, hair and nails, are one of the easiest organ systems to evaluate as it is the most accessible. However, mice are small, have lots of very fine hair of multiple types, and while major abnormalities are obvious, subtle ones, or the basis for these defects can be difficult to define. To assist in outlining basic approaches to evaluating mice clinically as well as microscopically with the help of a pathologist, methods are provided here that are used routinely in many laboratories. The mouse is a very useful mammalian model system for studying normal and abnormal (disease) development and there is a high degree of correlation with not only human biology and medicine but that of most other mammalian species. Utilizing basic approaches standardizes analysis and provides quality samples for analysis.
    No preview · Article · Sep 2014
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    ABSTRACT: SHARPIN is a key regulator of NFKB and integrin signaling. Mice lacking Sharpin develop a phenotype known as chronic proliferative dermatitis (CPDM), typified by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. Rag1(-/-) mice, which lack mature B and T cells, were crossed with Sharpin(-/-) mice to examine the role of lymphocytes in CDPM. Although inflammation in the lungs, liver, and joints was reduced in these double mutant mice, dermatitis was not reduced in the absence of functional lymphocytes, suggesting that lymphocytes are not primary drivers of the inflammation in the skin. Type 2 cytokine expression is increased in CPDM. In an attempt to reduce this aspect of the phenotype, Il4ra(-/-) mice, unresponsive to both IL4 and IL13, were crossed with Sharpin(-/-) mice. Double homozygous Sharpin(-/-) , Il4ra(-/-) mice developed an exacerbated granulocytic dermatitis, acute system inflammation, as well as hepatic necrosis and mineralization. High expression of CHI3L4, normally seen in CPDM skin, was abolished in Sharpin(-/-) , Il4ra(-/-) double mutant mice indicating the crucial role of IL4 and IL13 in the expression of this protein. Cutaneous eosinophilia persisted in Sharpin(-/-) , Il4ra(-/-) mice, although expression of Il5 mRNA was reduced and the expression of Ccl11 and Ccl24 was completely abolished. TSLP and IL33 were both increased in the skin of Sharpin(-/-) mice and this was maintained in Sharpin(-/-) , Il4ra(-/-) mice suggesting a role for TSLP and IL33 in the eosinophilic dermatitis in SHARPIN-deficient mice. These studies indicate that cutaneous inflammation in SHARPIN-deficient mice is autoinflammatory in nature developing independently of B and T lymphocytes, while the systemic inflammation seen in CPDM has a strong lymphocyte-dependent component. Both the cutaneous and systemic inflammation is enhanced by loss of IL4 and IL13 signaling indicating that these cytokines normally play an anti-inflammatory role in SHARPIN-deficient mice.
    Full-text · Article · Jan 2014 · PLoS ONE
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    ABSTRACT: Alopecia areata (AA) is a cell-mediated autoimmune disease that targets actively growing hair follicles in mammals, including humans and mice. Development of the C3H/HeJ spontaneous mouse model AA nearly 20 years ago provided a much needed tool to test the hypotheses and ultimately serve as a preclinical model for drug testing. Discoveries in both human AA patients and the mouse model supported each other and lead to discoveries on the incredibly complex genetic basis of this disease. The discovery that A/J, MRL/MpJ, SJL/J, and SWR/J strains also develop AA now allows genome-wide association mapping studies to expand the list of genes underlying this disease. Potential new targets for unraveling the pathogenesis of AA include the role of retinoic acid metabolism in the severity of disease and hair shaft proteins that may be either the inciting antigen or ultimate target of the immune reaction leading to breakage of the shaft causing clinical alopecia. Comparing these model systems with human and mouse clinical disease, for both discovery and validation of the discoveries, continues to resolve the complex questions surrounding AA.
    No preview · Article · Dec 2013 · Journal of Investigative Dermatology Symposium Proceedings
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    ABSTRACT: Detailed histopathological diagnoses of inbred mouse strains are important for interpreting research results and defining novel models of human diseases. The aim of this study was to histologically detect lesions affecting the KK/HlJ inbred strain. Mice were examined at 6, 12, and 20 months of age and near natural death (ie, moribund mice). Histopathological lesions were quantified by percentage of affected mice per age group and sex. Predominant lesions were mineralization, hyperplasia, and fibro-osseous lesions. Mineralization was most frequently found in the connective tissue dermal sheath of vibrissae, the heart, and the lung. Mineralization was also found in many other organs but to a lesser degree. Hyperplasia was found most commonly in the pancreatic islets, and fibro-osseous lesions were observed in several bones. The percentage of lesions increased with age until 20 months. This study shows that KK/HlJ mice demonstrate systemic aberrant mineralization, with greatest frequency in aged mice. The detailed information about histopathological lesions in the inbred strain KK/HlJ can help investigators to choose the right model and correctly interpret the experimental results.
    No preview · Article · Sep 2013 · Veterinary Pathology
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    ABSTRACT: Abbreviations: AA, alopecia areata; Abcc6 (mouse gene), ABCC6 (human gene), ATP-binding cassette subfamily C, member 6, gene; Dyscalc1–4, dystrophic cardiac calcinosis 1–4; PXE, pseudoxanthoma elasticum; QTL, quantitative trait loci
    Preview · Article · Jun 2013 · Journal of Investigative Dermatology
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    Lloyd E King · Kathleen A Silva · Victoria E Kennedy · John P Sundberg
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    ABSTRACT: Abbreviations: AA, alopecia areata; AU, alopecia universalis
    Preview · Article · Jun 2013 · Journal of Investigative Dermatology
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    ABSTRACT: Abbreviations: ATP-binding cassette, subfamily C, member 6 (gene symbol: Abcc6, mice; ABCC6, human; protein symbol for both: ABCC6); secreted phosphoprotein 1 (gene symbol: SPP1, human); SUMO/sentrin-specific peptidase 6 (gene symbol: SENP6, human; Senp6, mouse); xylosyltransferase I (gene symbol: XYLT, human; Xylt1 and 2, mouse); Casr, calcium-sensing receptor; DCC, dystrophic cardiac calcinosis; PXE, pseudoxanthoma elasticum; SNP, single-nucleotide polymorphism
    Preview · Article · Sep 2012 · Journal of Investigative Dermatology
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    Yanhua Liang · Kathleen A Silva · Victoria Kennedy · John P Sundberg
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    ABSTRACT: Three methods are currently available to reconstitute hair follicles in mice. Direct comparisons have yet to be made to determine which method is most efficient. In this study, mouse epithelial cells (MECs) and mouse dermal cells (MDCs) were grafted onto the dorsal skin of nude mice using the chamber, flap or patch assays. Comparisons were made based on gross, scanning electron microscopic and histological observations. MDCs alone induced hair follicle reconstitution with the production of hairs yielding false-positive results caused by contamination by hair follicle remnants. Neither primary MECs nor cultured MDCs alone formed hair follicles but did result in hair follicle formation when mixed together. Frozen MECs or MDCs resulted in decreased hair follicle-inductive activity but could still regenerate hairs. The hair patch assay was the quickest model (20±3 days) to determine whether cell mixtures would reconstitute hair follicles that produce hairs; however, the hair follicles were randomly orientated and often associated with foreign body granulomas. The flap assay took the longest time (29±2 days) to produce follicles and hairs to develop with a clinically natural appearance, but an epidermal sheet was needed. The chamber assay was the most labour-intensive and cell number-dependent procedure but follicles developed in a dense, clinically normal manner.
    Preview · Article · Dec 2011 · Experimental Dermatology
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    ABSTRACT: Genetic influences that underlie spontaneous lung oncogenesis are poorly understood. The objective of this study was to determine the genetic influences on spontaneous pulmonary adenoma frequency and severity in 28 strains of mice as part of a large-scale aging study conducted at the Jackson Aging Center (http://agingmice.jax.org/). Genome-wide association studies were conducted in these strains with both low-density (132,000) and high-density (4,000,000) panel of single-nucleotide polymorphisms (SNP). Our analysis revealed that adenomas were relatively less frequent and less severe in females than males, and that loci implicated in frequency and severity were often different between male and female mice. While some of the significant loci identified mapped to genomic locations known to be responsible for carcinogen-induced cancers (e.g., Pas1), others were unique to our study. In particular, Fat4 was influential in males and Tsc22d1 was influential in females. SNPs implicated were predicted to alter amino acid sequence and change protein function. In summary, our results suggested that genetic influences that underlie pulmonary adenoma frequency are dependent on gender, and that Fat4 and Tsc22d1 are likely candidate genes to influence formation of spontaneous pulmonary adenoma in aging male and female mice, respectively.
    Preview · Article · Jul 2011 · Cancer Research
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    ABSTRACT: Inbred mice provide a unique tool to study aging populations because of the genetic homogeneity within an inbred strain, their short life span, and the tools for analysis which are available. A large-scale longitudinal and cross-sectional aging study was conducted on 30 inbred strains to determine, using histopathology, the type and diversity of diseases mice develop as they age. These data provide tools that when linked with modern in silico genetic mapping tools, can begin to unravel the complex genetics of many of the common chronic diseases associated with aging in humans and other mammals. In addition, novel disease models were discovered in some strains, such as rhabdomyosarcoma in old A/J mice, to diseases affecting many but not all strains including pseudoxanthoma elasticum, pulmonary adenoma, alopecia areata, and many others. This extensive data set is now available online and provides a useful tool to help better understand strain-specific background diseases that can complicate interpretation of genetically engineered mice and other manipulatable mouse studies that utilize these strains.
    Full-text · Article · Jun 2011