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Search Results: 1 - 10 of 229345 matches for " John P. Sundberg "
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The mouse as a model for understanding chronic diseases of aging: the histopathologic basis of aging in inbred mice
John P. Sundberg,Annerose Berndt,Beth A. Sundberg,Kathleen A. Silva
Pathobiology of Aging & Age-related Diseases , 2011, DOI: 10.3402/pba.v1i0.7179
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.
Rhabdomyosarcomas in Aging A/J Mice
Roger B. Sher, Gregory A. Cox, Kevin D. Mills, John P. Sundberg
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023498
Abstract: Rhabdomyosarcomas (RSCs) are skeletal muscle neoplasms found in humans and domestic mammals. The A/J inbred strain developed a high frequency (between 70–80%) of adult pleomorphic type (APT) RSC at >20 months of age while BALB/cByJ also develop RSC but less frequently. These neoplasms invaded skeletal muscle surrounding either the axial or proximal appendicular skeleton and were characterized by pleomorphic cells with abundant eosinophilic cytoplasm, multiple nuclei, and cross striations. The diagnosis was confirmed by detection of alpha-sarcomeric actin and myogenin in the neoplastic cells using immunocytochemistry. The A/J strain, but not the related BALB/c substrains, is also characterised by a progressive muscular dystrophy homologous to limb-girdle muscular dystrophy type 2B. The association between the development of RSC in similar muscle groups to those most severely affected by the progressive muscular dystrophy suggested that these neoplasms developed from abnormal regeneration of the skeletal muscle exacerbated by the dysferlin mutation. Transcriptome analyses of RSCs revealed marked downregulation of genes in muscular development and function signaling networks. Non-synonymous coding SNPs were found in Myl1, Abra, Sgca, Ttn, and Kcnj12 suggesting these may be important in the pathogenesis of RSC. These studies suggest that A strains of mice can be useful models for dissecting the molecular genetic basis for development, progression, and ultimately for testing novel anticancer therapeutic agents dealing with rhabdomyosarcoma.
SHARPIN Is Essential for Cytokine Production, NF-κB Signaling, and Induction of Th1 Differentiation by Dendritic Cells
Zhe Wang, Anna Sokolovska, Rosemarie Seymour, John P. Sundberg, Harm HogenEsch
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031809
Abstract: Spontaneous mutations of the Sharpin (SHANK-associated RH domain-interacting protein, other aliases: Rbckl1, Sipl1) gene in mice result in systemic inflammation that is characterized by chronic proliferative dermatitis and dysregulated secretion of T helper1 (Th1) and Th2 cytokines. The cellular and molecular mechanisms underlying this inflammatory phenotype remain elusive. Dendritic cells may contribute to the initiation and progression of the phenotype of SHARPIN-deficient mice because of their pivotal role in innate and adaptive immunity. Here we show by flow cytometry that SHARPIN- deficiency did not alter the distribution of different DC subtypes in the spleen. In response to TOLL-like receptor (TLR) agonists LPS and poly I:C, cultured bone marrow-derived dendritic cells (BMDC) from WT and mutant mice exhibited similar increases in expression of co-stimulatory molecules CD40, CD80, and CD86. However, stimulated SHARPIN-deficient BMDC had reduced transcription and secretion of pro-inflammatory mediators IL6, IL12P70, GMCSF, and nitric oxide. Mutant BMDC had defective activation of NF-κB signaling, whereas the MAPK1/3 (ERK1/2) and MAPK11/12/13/14 (p38 MAP kinase isoforms) and TBK1 signaling pathways were intact. A mixed lymphocyte reaction showed that mutant BMDC only induced a weak Th1 immune response but stimulated increased Th2 cytokine production from allogeneic na?ve CD4+ T cells. In conclusion, loss of Sharpin in mice significantly affects the immune function of DC and this may partially account for the systemic inflammation and Th2-biased immune response.
Loss of Function of the Mouse Sharpin Gene Results in Peyer’s Patch Regression
Rosemarie Seymour, Bobbi-Jo Shirley, Harm HogenEsch, Leonard D. Shultz, John P. Sundberg
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055224
Abstract: Peyer’s patches (PP) are an important component in the immune response against intestinal pathogens. Two independent, spontaneous mutations in the mouse Sharpin gene (Sharpincpdm and Sharpincpdm-Dem) result in the absence of PP and disrupted splenic white pulp in adult mice, although a full complement of lymph nodes is present. Here we report that rudimentary PP begin to develop in Sharpincpdm mice during embryogenesis, but lack the organizational patterns that are typical of this tissue. In the present study, small intestines examined at weekly intervals from birth to maturity showed spontaneous regression of PP in mutant mice with concurrent infiltration of granulocytes. At 5 to 6 weeks of age, only indistinct remnants of granulocytic accumulations remain. Transplantation of normal bone marrow into Sharpincpdm mice at 7 days of age did not prevent regression of PP in bone marrow chimeras examined at 7 to 8 weeks of age. These findings indicate that SHARPIN expression is required for the normal development and maintenance, but not initiation, of PP.
Mouse Models for Pseudoxanthoma Elasticum: Genetic and Dietary Modulation of the Ectopic Mineralization Phenotypes
Qiaoli Li, Haitao Guo, David W. Chou, Annerose Berndt, John P. Sundberg, Jouni Uitto
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089268
Abstract: Pseudoxanthoma elasticum (PXE), a heritable ectopic mineralization disorder, is caused by mutations in the ABCC6 gene. Null mice (Abcc6?/?) recapitulate the genetic, histopathologic and ultrastructural features of PXE, and they demonstrate early and progressive mineralization of vibrissae dermal sheath, which serves as a biomarker of the overall mineralization process. Recently, as part of a mouse aging study at The Jackson Laboratory, 31 inbred mouse strains were necropsied, and two of them, KK/HlJ and 129S1/SvImJ, were noted to have vibrissae dermal mineralization similar to Abcc6?/? mice. These two strains were shown to harbor a single nucleotide polymorphism (rs32756904) in the Abcc6 gene, which resulted in out-of-frame splicing and marked reduction in ABCC6 protein expression in the liver of these mice. The same polymorphism is present in two additional mouse strains, DBA/2J and C3H/HeJ, with similar reduction in Abcc6 protein levels, yet these mice did not demonstrate tissue mineralization when kept on standard rodent diet. However, all four mouse strains, when placed on experimental diet enriched in phosphate and low in magnesium, developed extensive ectopic mineralization. These results indicate that the genetic background of mice and the mineral composition of their diet can profoundly modulate the ectopic mineralization process predicated on mutations in the Abcc6 gene. These mice provide novel model systems to study the pathomechanisms and the reasons for strain background on phenotypic variability of PXE.
Evidence for Hox-specified positional identities in adult vasculature
Nathanael D Pruett, Richard P Visconti, Donna F Jacobs, Dimitri Scholz, Tim McQuinn, John P Sundberg, Alexander Awgulewitsch
BMC Developmental Biology , 2008, DOI: 10.1186/1471-213x-8-93
Abstract: We demonstrate that conventional reporter gene analysis in transgenic mice is a useful approach for defining highly complex Hox expression patterns in the adult vascular network as exemplified by our lacZ reporter gene models for Hoxa3 and Hoxc11. These mice revealed expression in subsets of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) located in distinct regions of the vasculature that roughly correspond to the embryonic expression domains of the two genes. These reporter gene patterns were validated as authentic indicators of endogenous gene expression by immunolabeling and PCR analysis. Furthermore, we show that persistent reporter gene expression in cultured cells derived from vessel explants facilitates in vitro characterization of phenotypic properties as exemplified by the differential response of Hoxc11-lacZ-positive versus-negative cells in migration assays and to serum.The data support a conceptual model of Hox-specified positional identities in adult blood vessels, which is of likely relevance for understanding the mechanisms underlying regional physiological diversities in the cardiovascular system. The data also demonstrate that conventional Hox reporter gene mice are useful tools for visualizing complex Hox expression patterns in the vascular network that might be unattainable otherwise. Finally, these mice are a resource for the isolation and phenotypic characterization of specific subpopulations of vascular cells marked by distinct Hox expression profiles.The Hox transcriptional regulators are known to play a critical role in establishing positional identities during embryonic patterning [1], whereas in postnatal and adult tissues, their functions are largely subject to speculation [2]. This also pertains to the adult cardiovascular system, although Hox genes are considered prime candidates for determining phenotypic characteristics of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) during vasculogenesis and vascu
Proteotypic classification of spontaneous and transgenic mammary neoplasms
Igor Mikaelian, Natalie Blades, Gary A Churchill, Karen Fancher, Barbara B Knowles, Janan T Eppig, John P Sundberg
Breast Cancer Research , 2004, DOI: 10.1186/bcr930
Abstract: Expression patterns for terminal differentiation markers were used to characterize tumor types and to study tumor progression in transgenic mouse models of mammary neoplasia (mice overexpressing Neu (Erbb2), Hras, Myc, Notch4, SV40-TAg, Tgfa, and Wnt1), in spontaneous mammary carcinomas, and in mammary neoplasms associated with infection by the mouse mammary tumor virus (MMTV).On the basis of the expression of terminal differentiation markers, three types of neoplasm were identified: first, simple carcinomas composed exclusively of cells with a luminal phenotype are characteristic of neoplasms arising in mice transgenic for Neu, Hras, Myc, Notch4, and SV40-TAg; second, 'complex carcinomas' displaying luminal and myoepithelial differentiation are characteristic of type P tumors arising in mice transgenic for Wnt1, neoplasms arising in mice infected by the MMTV, and spontaneous adenosquamous carcinomas; and third, 'carcinomas with epithelial to mesenchymal transition (EMT)' are a characteristic feature of tumor progression in Hras-, Myc-, and SV40-TAg-induced mammary neoplasms and PL/J and SJL/J mouse strains, and display de novo expression of myoepithelial and mesenchymal cell markers. In sharp contrast, EMT was not detected in papillary adenocarcinomas arising in BALB/cJ mice, spontaneous adenoacanthomas, neoplasms associated with MMTV-infection, or in neoplasms arising in mice transgenic for Neu and Wnt1.Immunohistochemical profiles of complex neoplasms are consistent with a stem cell origin, whereas simple carcinomas might originate from a cell committed to the luminal lineage. In addition, these results suggest that the initiating oncogenic events determine the morphologic features associated with cancer progression because EMT is observed only in certain types of neoplasm.Architectural and cytological patterns have been the basis for mammary tumor categorization for more than a century [1]. Over the past 20 years, immunohistochemistry has added a molecular dimen
Differentiating Inbred Mouse Strains from Each Other and Those with Single Gene Mutations Using Hair Proteomics
Robert H. Rice, Katie M. Bradshaw, Blythe P. Durbin-Johnson, David M. Rocke, Richard A. Eigenheer, Brett S. Phinney, John P. Sundberg
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051956
Abstract: Mutant laboratory mice with distinctive hair phenotypes are useful for identifying genes responsible for hair diseases. The work presented here demonstrates that shotgun proteomic profiling can distinguish hair shafts from different inbred mouse strains. For this purpose, analyzing the total hair shaft provided better discrimination than analyzing the isolated solubilized and particulate (cross-linked) fractions. Over 100 proteins exhibited significant differences among the 11 strains and 5 mutant stocks across the wide spectrum of strains surveyed. Effects on the profile of single gene mutations causing hair shaft defects were profound. Since the hair shaft provides a discrete sampling of the species proteome, with constituents serving important functions in epidermal appendages and throughout the body, this work provides a foundation for non-invasive diagnosis of genetic diseases of hair and perhaps other tissues.
Disheveled Hair and Ear (Dhe), a Spontaneous Mouse Lmna Mutation Modeling Human Laminopathies
Paul R. Odgren,Craig H. Pratt,Carole A. MacKay,April Mason-Savas,Michelle Curtain,Lindsay Shopland,Tsutomu Ichicki,John P. Sundberg,Leah Rae Donahue
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009959
Abstract: Investigations of naturally-occurring mutations in animal models provide important insights and valuable disease models. Lamins A and C, along with lamin B, are type V intermediate filament proteins which constitute the proteinaceous boundary of the nucleus. LMNA mutations in humans cause a wide range of phenotypes, collectively termed laminopathies. To identify the mutation and investigate the phenotype of a spontaneous, semi-dominant mutation that we have named Disheveled hair and ear (Dhe), which causes a sparse coat and small external ears in heterozygotes and lethality in homozygotes by postnatal day 10.
Avian papillomaviruses: the parrot Psittacus erithacus papillomavirus (PePV) genome has a unique organization of the early protein region and is phylogenetically related to the chaffinch papillomavirus
Ruth Tachezy, Annabel Rector, Marta Havelkova, Elke Wollants, Pierre Fiten, Ghislain Opdenakker, A Bennett Jenson, John P Sundberg, Marc Van Ranst
BMC Microbiology , 2002, DOI: 10.1186/1471-2180-2-19
Abstract: The PePV genome (7304 basepairs) differs from other papillomaviruses, in that it has a unique organization of the early protein region lacking classical E6 and E7 open reading frames. Phylogenetic comparison of the PePV sequence with partial E1 and L1 sequences of the chaffinch (Fringilla coelebs) papillomavirus (FPV) reveals that these two avian papillomaviruses form a monophyletic cluster with a common branch that originates near the unresolved center of the papillomavirus evolutionary tree.The PePV genome has a unique layout of the early protein region which represents a novel prototypic genomic organization for avian papillomaviruses. The close relationship between PePV and FPV, and between their Psittaciformes and Passeriformes hosts, supports the hypothesis that papillomaviruses have co-evolved and speciated together with their host species throughout evolution.Papillomaviruses are a large group of pathogens that cause epithelial proliferations in a wide spectrum of vertebrate species. More than 100 different human papillomaviruses (HPV) have been isolated [1,2]. Such an extensive genotype variety has not yet been detected in nonhuman species, although papillomavirus genomes have been isolated from many species where careful investigational efforts were made [3,4]. Most papillomaviruses appear to be species-specific or at least restricted to infection of closely related animals within the same genus. Papillomavirus genomes have been cloned from 20 mammalian host species. Thus far, only two avian papillomavirus genomes were cloned, one from a chaffinch and the second from a parrot papilloma. To date no complete avian papillomavirus genome had been sequenced.In a large survey of 25,000 captured chaffinches (Fringilla coelebs) in the Netherlands, papillomas were found on the foot or tarsometatarsus (the bare part of the leg) of 1.3% of the birds [5]. The DNA of a Fringilla PV (FPV) was isolated from such skin papillomas, and two partial sequences of FPV, totaling
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