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Babaie, Yasmin. "A murine model for haemangioblast transplantation." Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/23691.
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A promoter trap strategy was used to target a single allele of the flk-1 gene with one of two reporter constructs. One placed the EGFP reporter under flk-1 transcriptional control, while the other transcribed the selectable HPRT enzyme, which could be used to isolate flk-1 expressing cells in the HM1 hprt deficient ES cell line. Homologous recombination was successfully achieved with both targeting vectors. HPRT targeted selectable lines were successfully isolated. All lines showed appropriate transgene expression at high enough levels for effective HAT selection to isolate pure populations of flk-1 expressing cells. Two methods of deriving haemangioblastic progenitors from ES cells were tested for their efficacy of the isolation of a pure haemangioblast population based on the expression of flk-1. Methylcellulose cultures were found to be highly variable and problematic to carry out successfully whereas monolayer differentiation on collagen IV was more consistent. This system was then used to optimise the differentiation and selection regime applied to the flk-1/HPRT targeted cells in an attempt to isolate a pure haemangioblast progenitor population. Flk-1/HPRT targeted cells were marked with a constitutive GFP transgene, differentiated and selected for flk-1/HPRT expression on collagen IV. The selected cells were injected into the blastocyst stage embryo to see whether a developmentally more advanced cell population would survive and contribute to the expected cell lineages. Contribution of the GFP marked cells was observed in mesodermal and highly vascularised organs such as the heart, liver and kidney but was absent from the ectodermally derived brain. Expression was strongly localised around regions of vacularisation.
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Watkins, Alan D. "A murine model of pulmonary inflammation." Thesis, University of Southampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395963.
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Zychlinska, Magdalena. "Murine Model System for EBV-related Diseases." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-73499.
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Barnard, Amanda Louise. "A murine model for immunotherapy of melanoma." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298460.
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Levison, Scott. "Characterization of a murine model of colitis." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/characterization-of-a-murine-model-of-colitis(4b966667-a763-4bcc-8896-7a157cf3d3dd).html.
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Inflammatory bowel disease (IBD) represents a complex spectrum of gastrointestinal diseases. Incorporating Crohn's disease (CD) and ulcerative colitis (UC), IBD is characterised by recurrent and chronic inflammation, significant morbidity, and an increasing global prevalence. Scientific advances regarding the aetiology, pathogenesis and treatment of these relapsing immune-mediated diseases have developed in parallel to the study of experimental models of intestinal inflammation. The correlation of phenotype, histology and immune response with mucosal gene expression, permits the investigation of induced pathology for human translation. Trichuris muris (mouse whipworm) infection induces chronic colitis in susceptible strains (e.g. AKR). Chronic disease displays both a polarised CD4+ T-helper1 (TH1) immune response and histological, transmural colonic inflammation. Conversely, resistant mouse strains (e.g. BALB/c) exhibit transient infection and inflammation which quickly resolves under a presiding TH2 response. Work presented in this thesis investigates differential gene expression and biological pathways central to colonic outcome, and the genetic basis of chronic T. muris-induced colitis. This thesis demonstrates that the phenotypic and transcriptional profile of the T. muris model shared many similarities to widely used experimental models of colonic inflammation and to human IBD. Mice susceptible to chronic colonic inflammation displayed functional gene expression differences to those of resistant mice, including the up-regulation of pro-inflammatory, apoptosis and chemokine signalling pathway genes. Cellular homeostasis pathways and tight junction molecules were conversely down-regulated. Infected AKR demonstrated predominant TH1/ TH17 transcriptional activity, presenting this model as a platform to examine biological commonalities among chronic colitides. A Quantitative Trait Locus (QTL) study, performed by crossbreeding resistant and susceptible strains to T. muris infection, then identified key autosomal loci linked to chronic disease. Genes associated with known biological pathways, differential gene expression, and parental strain single nucleotide polymorphisms provided a novel and powerful strategy to reduce the number of candidate genes for further analysis. Of 7 T. muris (TM) QTL identified, 3 displayed overlap with other murine studies of parasite susceptibility. A separate locus, TM3, demonstrated overlap with published QTL in 3 unrelated experimental models of colitis and overlaid the Cdcs1 locus. TM3 possessed 33 significantly transcribed polymorphic genes (e.g. Ptpn22, Fcgr1, Rorc, Vcam1 and Vav3). Phenotypic pathway analysis, text mining and time-course qPCR all highlighted Vav3 (Human 1p13.3, murine Chr3 101.9 MB) as a key biological candidate in colitis susceptibility. As a final test of relevance to human disease, clinically proven IBD medications were administered to AKR mice post-T. muris infection, at a time-point when chronic disease was well established. Anti-TNFα Ab and corticosteroid therapy were shown to suppress TH1-driven experimental colitis, without affecting parasitic infection. Additionally, anti-TNFα Ab treatment was found to reduce pro-inflammatory macrophages yet preserve regulatory alternatively activated macrophage numbers within the colon. A previously unreported finding. Sharing biological commonalities with human CD, Trichuris muris colitis represents an advanced and tractable murine model for understanding the pathobiological mechanisms of chronic inflammatory disease. The key facet of this model is that despite identical injury some inbred mouse strains develop chronic colitis whilst others recover quickly and fully. The identification of differential mechanisms which govern outcome and a new platform to investigate novel targets of disease and disease therapy has implications for gastrointestinal inflammatory diseases and mucosal immunology.
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Healy, D. M. "Comparative pathology of Lyssaviruses in a murine model." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546358.
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Beer, Abigail J. "Development of an Inducible c-MYC Murine Model." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1602754882137456.
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Gibbons, Peter Luke. "Development of a Pharmacodynamic Model of Murine Malaria." Thesis, Curtin University, 2015. http://hdl.handle.net/20.500.11937/1031.
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The rational design of antimalarial therapies has historically been compromised by a paucity of pharmacodynamic data contributing to resistance through deployment of suboptimal doses. This thesis demonstrates a modified P. berghei murine malaria model for collecting detailed in vivo pharmacodynamic data and novel in silico mathematical model enabling optimisation of dosing and combination therapy. These models contribute to preclinical knowledge and provide the potential to assist in the development of methods to optimise clinical treatment.
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Luzzi, Keith J. "Quantification of metastatic inefficiency in a murine liver model." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/mq21109.pdf.
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Holland, T. W. C. "The pathogenesis of a murine model of rheumatoid arthritis." Thesis, University of Nottingham, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.330136.
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Davami, Mohammad Hassan. "Immunology of crytopsoridiosis : studies with a murine infection model." Thesis, London School of Hygiene and Tropical Medicine (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267888.
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Franklin, Sarah Louise. "The extracellular matrix in a model of murine scrapie." Thesis, University of Bristol, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440256.
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Hynes, Ann Marie. "Investigating nephronophthisis using a novel murine and cell model." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2370.
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Nephronophthisis (NPHP) is a major cause of pediatric renal failure. Currently there is little understanding of the aetiology of the disease. In order to identify the molecular events leading to NPHP, we have created a novel mutant mouse strain containing a truncating mutation in the Cep290 gene. Patients with mutations in CEP290 present with a ciliopathy phenotype that includes retinal dystrophy, cerebellum defects and NPHP. Characterisation of Cep290LacZ/LacZ mice confirms that they display all the features of the human condition. Microarray analysis of newborn kidney tissue was used to explore initiating events leading to NPHP. Ciliopathies have recently been associated with either disrupted Wingless integrated (Wnt) or sonic hedgehog (Shh) signaling. We show that mutant kidneys display abnormal Shh signaling in the absence of Wnt signaling abnormalities. Primary cell cultures of collecting duct (CDT) cells (isolated from Cep290LacZ/LacZ mice and wild-type litter mates crossed with the “immorto” mouse) were established and characterised. CDT cells expressed the mineral corticoid receptor (MR) and the epithelial sodium channel (ENaC) alpha subunit. The CDT cell lines formed epithelial layers and formed tubules when maintained in 3D culture media. Cep290LacZ/LacZ CDT cells displayed ciliogenesis abnormalities as well as abnormal spheroids with loss of lumen when grown in 3D culture. Pharmacological activation of Shh signaling (purmorphamine) partially rescues the spheroid and ciliogenesis defects in Cep290LacZ/LacZ CDT cells. This implicates abnormal Shh signaling in the onset of NPHP and suggests that targeted treatment of Shh antagonists have therapeutic potential.
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Rutter, Erica M., Tracy L. Stepien, Barrett J. Anderies, Jonathan D. Plasencia, Eric C. Woolf, Adrienne C. Scheck, Gregory H. Turner, et al. "Mathematical Analysis of Glioma Growth in a Murine Model." NATURE PUBLISHING GROUP, 2017. http://hdl.handle.net/10150/624455.
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Five immunocompetent C57BL/6-cBrd/cBrd/Cr (albino C57BL/6) mice were injected with GL261-luc2 cells, a cell line sharing characteristics of human glioblastoma multiforme (GBM). The mice were imaged using magnetic resonance (MR) at five separate time points to characterize growth and development of the tumor. After 25 days, the final tumor volumes of the mice varied from 12 mm(3) to 62 mm(3), even though mice were inoculated from the same tumor cell line under carefully controlled conditions. We generated hypotheses to explore large variances in final tumor size and tested them with our simple reaction-diffusion model in both a 3-dimensional (3D) finite difference method and a 2-dimensional (2D) level set method. The parameters obtained from a best-fit procedure, designed to yield simulated tumors as close as possible to the observed ones, vary by an order of magnitude between the three mice analyzed in detail. These differences may reflect morphological and biological variability in tumor growth, as well as errors in the mathematical model, perhaps from an oversimplification of the tumor dynamics or nonidentifiability of parameters. Our results generate parameters that match other experimental in vitro and in vivo measurements. Additionally, we calculate wave speed, which matches with other rat and human measurements.
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Yahya, Mohd Danial. "Immunological studies of malondialdehyde in a murine lupus model." Diss., The University of Arizona, 1992. http://hdl.handle.net/10150/185941.
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Malondialdehyde (MDA) is a highly reactive three carbon dialdehyde produced as a byproduct of polyunsaturated fatty acid peroxidation and arachidonic acid metabolism. MDA readily forms intermolecular or intramolecular cross-linkages with chemical groups on various molecules and alters both their physicochemical properties and immunogenicity. In vivo these changes may generate neoantigens that consequently can elicit an immune response involving antibody production and immune complex formation. In this study the possible role of an anti-MDA immune response in the pathogenesis of disease in lupus-prone MRL/lpr mice was investigated. Physicochemical alterations to mouse serum albumin (MSA) were characterized and reliable immunological assays were developed to measure this immune response. MDA readily bound to amino groups on MSA, formed epitopes in a dose-dependent manner and altered its antigenicity. The presence of a specific anti-MDA response in MRL/lpr was verified using an enzyme-linked immunosorbent assay (ELISA) and inhibition ELISA. The immune complex capture assay, using MDA-specific polyclonal antiserum as capture antibody, detected significantly higher levels of MDA-containing immune complexes in sera of MRL/lpr mice compared to non-lupus strains. A time course study showed that in comparison to anti-dsDNA antibodies, anti-MDA antibodies were produced earlier and in significantly higher levels. These antibodies were found predominantly in the complement-fixing IgG₂ₐ and IgG₂(b) subclasses. Levels of IgG anti-MDA antibodies and MDA-containing immune complexes were highest at 4 months age. Western blot analysis revealed the presence of a 100 kilodalton MDA-modified protein in sera of MRL/lpr mice at 3 and 5 months of age but not at 1 month. In sera from non-lupus MRL/+ mice the level of MDA-modification of serum proteins was considerably lower. Vitamin E treatment for up to 16 weeks did not significantly affect the anti-MDA response, MDA-containing immune complex levels nor modification of serum proteins by MDA. Immunohistochemical studies demonstrated the presence of MDA-containing immune complexes, IgG and complement deposition in renal glomeruli. This is the first demonstration of circulating MDA-specific antibodies, MDA-containing immune complexes and MDA-modified serum proteins in MRL/lpr mice. This response may contribute to disease pathogenesis in these mice via formation and subsequent tissue deposition of immune complexes containing anti-MDA antibodies and MDA adducts.
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Laprano, Nicola. "Metabolic alterations in a murine model of Barth syndrome." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/9105/.
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Barth syndrome (BTHS) is a rare monogenic disease characterized by cardiomyopathy, skeletal myopathy and neutropenia, caused by mutations in the Xq28 locus. Mutations in the locus result in the loss of function of the Tafazzin protein (Taz), a transacylase responsible for the final step in the production of mature cardiolipin (CL). CL is a fundamental component of the inner mitochondrial membrane, where it cooperates in the maintenance of membrane stability and in various cellular processes such as mitochondrial respiration, autophagy and reactive oxygen species sensing. Using a novel murine model of BTHS, we investigated the mitochondrial phenotype, the metabolic signature and the gene expression profile in the heart of Taz knockout (KO) mice. We identified extensive heart-specific changes in the structure and composition of the mitochondria accompanied by alterations of the metabolome and gene expression. The alterations are specific to the adult, so probably derive from a developmental process happening after birth. The alteration of the gene expression seems to indicate activation of the unfolded protein response, suggesting an effect of stress response pathways in the cellular processes which underlie Barth syndrome.
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Moore, Brioni R. "Pharmacodynamic studies of antimalarial drugs in a murine malaria model." Thesis, Curtin University, 2011. http://hdl.handle.net/20.500.11937/699.
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Murine malaria models have proved to be a valuable preclinical tool, particularly in the development of new concepts in the research of human malaria. Plasmodium berghei (P. berghei), is the most extensively studied and manipulated rodent parasite and as a laboratory model, is largely selected for studies relating to developmental biology of parasites and investigation into new and innovative drug therapies. Whilst direct extrapolation from rodent biology to human malarias should be generally avoided, murine malaria models may contribute a greater understanding of important characteristics for antimalarial drug development and drug efficacy studies. However, there is currently a paucity of murine pharmacological data available for both commonly used, and emerging, antimalarial therapies. The findings of the studies in this thesis are seen as an important contribution to the preclinical knowledge of the investigated drugs which to date, have not been adequately studied.The aim of the thesis was to investigate the efficacy, pharmacokinetic and/or pharmacodynamic properties of various antimalarial drugs, in a P. berghei murine malaria model. Specific aims were to: (i) Evaluate the pharmacodynamic effects of dihydroartemisinin (DHA) in asplenic P. berghei infected mice. (ii) Investigate the pharmacokinetic and pharmacodynamic properties of single dose piperaquine (PQ) in healthy and P. berghei infected mice. (iii) Investigate the extended antimalarial effect of PQ concentrating on drug efficacy, re-inoculation outcomes and parasite viability. (iv) Evaluate the pharmacokinetic and pharmacodynamic properties of single and multiple doses of chloroquine (CQ) in healthy and P. berghei infected mice.Using an asplenic model of P. berghei malaria, the efficacy of single doses of DHA (0, 10, 30 and 100 mg/kg) were evaluated in uninfected and P. berghei infected, intact and asplenic mice. Haematology, liver biochemistry and histopathology were performed to investigate the responses of key organs to malaria infection. Whilst overall efficacy of single dose DHA in asplenic mice was shown to be similar to intact mice, the rate of parasite recrudescence after parasite nadir (20 h at all doses studied) was significantly higher in the asplenic mice, particularly at higher doses (30 and 100 mg/kg DHA). Histopathology of the liver and associated blood chemistries, demonstrated an increased stimulation of liver function during malaria infection in asplenic mice, when compared to intact mice.Whilst studying the pharmacokinetic and pharmacodynamic responses of PQ in the P. berghei malaria treatment model, particular focus was placed on (i) pharmacodynamic properties of single doses of PQ (0, 10, 30 and 90 mg/kg PQ phosphate (PQP)); (ii) pharmacokinetic parameters of PQ in healthy and P. berghei infected mice; (iii) efficacy of combined doses of 10 mg/kg PQP and 30 mg/kg DHA. Single dose administration of PQP resulted in a median survival time of 4, 10 and 54 days after doses of 0, 10 and 30 mg/kg PQP, respectively, while mice receiving a single 90 mg/kg dose showed a medium survival time exceeding 60 days (experimental endpoint). Pharmacokinetic analysis determined the elimination half-life of PQ in healthy and P. berghei infected mice was 18 and 16 days, respectively. Furthermore, extrapolation of PQ concentrations suggested that at 60 days the plasma drug concentration would be ineffective at suppressing the P. berghei infection (<10 μg/L). Combination of PQP and DHA resulted in a significantly lower parasite nadir (22 ± 12 fold) than for either drug given individually.Given that high dose PQP (90 mg/kg) demonstrated extended antimalarial efficacy, further invetsigations were pursued on drug efficacy, re-inoculation outcomes and parasite viability after a single 90 mg/kg dose of PQP. Investigation showed that after initial dosing, PQ concentrations were not adequate to suppress parasitaemia after 25 days. Furthermore, although viable parasites were present up to 90 days after drug administration, once these viable parasites were passaged into naive mice they were found to be generally resistant to PQ when exposed to the drug for a second time. Overall, PQ was found to have a substantial antimalarial effect in this model with this effect appearing to be sufficient for a host immunological response to be established thus resulting in the long term survival of P. berghei infected mice.Although CQ is widely used in preclinical animal studies, there is a paucity of comprehensive pharmacokinetic data of CQ in animal models. In this thesis robust pharmacokinetic and pharmacodynamic data of CQ is presentated after single and multiple dose administration of CQ in the P. berghei malaria model. The pharmacokinetics of desethyl-CQ (DECQ), the major active metabolite of CQ, were estimated. Pharmacodynamic data demonstrated that parasite nadir was reached 79 h after a single dose of 60 mg/kg CQ, with all mice developing parasite recrudescence. Multiple dose (5 x 50 mg/kg CQ; dosed every 24 h) administration resulted in parasitaemia falling below the limit of detection. Despite a short period of recrudescence (between 10 and 24 days after initial dose), parasitaemia remained undetectable until the experimental end point (35 days after the initial dose). Pharmacokinetic analysis determined an elimination half-life of 46.6 h in healthy mice and 99.3 h in malaria-infected mice (single dose data; non-compartmental analysis). The mean rate of formation of DCQ from CQ was 0.63 ± 0.55 h-1 with a formation half-life of 1.7 ± 1.0 h.Consequently, the drug efficacy, pharmacodynamic and pharmacokinetic data included in this thesis demonstrates that the current P. berghei murine malaria treatment model can be used as a valuable preclinical conceptual tool for the investigation of antimalarial drugs such as DHA, PQ and CQ.
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Dawson, Janet. "Development and characterisation of a murine model of chronic inflammation." Thesis, Royal Veterinary College (University of London), 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522191.
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Uno, Jennifer Kikue. "Bone Mineralization in a Murine Model of Inflammatory Bowel Disease." Diss., Tucson, Arizona : University of Arizona, 2006. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1650%5F1%5Fm.pdf&type=application/pdf.
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Cherelyn, Vella. "Coxsackie B4 virus infection of the pancreas - a murine model." Thesis, Queen Mary, University of London, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281620.
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Martin, Claire Adriana. "Mechanisms of arrhythmogenesis in a murine model of Brugada syndrome." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648347.
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Fonseca, Cátia Isabel Correia dos Reis. "Vaccine Targets in a Murine Model of Renal Cell Carcinoma." Doctoral thesis, Instituto de Ciências Biomédicas Abel Salazar, 2007. http://hdl.handle.net/10216/7210.
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Rose, Lisa. "Bioluminescence Imaging of Canine Osteosarcoma in an Orthotopic Murine Model." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429269876.
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Van, Andel Roger A. "The immunopathogenesis of clostridium piliforme evaluated in a murine model /." free to MU campus, to others for purchase, 1997. http://wwwlib.umi.com/cr/mo/fullcit?p9842572.
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Fonseca, Cátia Isabel Correia dos Reis. "Vaccine Targets in a Murine Model of Renal Cell Carcinoma." Tese, Instituto de Ciências Biomédicas Abel Salazar, 2007. http://hdl.handle.net/10216/7210.
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Carollo, Maria. "Investigation of chemokine receptor expression in an experimental model of chronic granulomatous inflammation." Thesis, Queen Mary, University of London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249652.
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Pereira, Beatriz Aparecida Soares. "Patogenicidade e imunogenicidade de isolados clínicos do complexo Paracoccidioides brasiliensis." Botucatu, 2019. http://hdl.handle.net/11449/181206.
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Orientador: Rinaldo Poncio MendesResumo: Introdução. A correlação entre gravidade da paracoccidioidomicose e patogenicidade e imunogenicidade dos fungos causadores tem sido pouco investigada e foi o objetivo deste estudo. Metodologia. As cincos cepas Pb192, Pb234, Pb326, Pb417 e Pb531 foram identificadas pelo seqüenciamento da região Exon 2 da gp43. A patogenicidade foi determinada pelo cálculo da dose letal 50% (DL50%) e pela contagem do número de unidades formadoras de colônias, realizada na sexta semana pós-infecção de camundongos BALB/c. A imunogenicidade foi determinada pela avaliação da resposta imune humoral específica, utilizando-se a reação de imunodifusão dupla em gel de ágar e da imunidade celular, determinada pela concentração das citocinas interleucina -2, interleucina-10, interferon-γ, fator de necrose tumoral – α e do fator de crescimento do endotélio vascular, em tecido pulmonar. Quatro amostras clínicas foram recém-isoladas de pacientes com paracoccidioidomicose, provenientes da Região de Botucatu - os isolados Pb234 e Pb417, de pacientes com a forma crônica moderada; o Pb326 de um caso com a forma aguda grave; e o Pb531, de um caso com a forma crônica grave. As demais cepas Pb192, Pb01 e 8334 foram cedidas pelo laboratório de Moléstias infecciosas. Resultados. As cepas Pb417 e Pb326 agruparam-se às cepas identificadas como P. brasiliensis S1a, a Pb531 às P. brasiliensis S1b e as cepas Pb234 e Pb192 às cepas depositadas como P. restrepiensis (PS3). Os resultados demonstraram correlação direta entre ... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Introduction. The investigation of paracoccidioidomycosis and pathogenicity and immunogenicity of the provoking fungi has been little investigated and was the objective of this study. Methodology. As strains, Pb192, Pb234, Pb326, Pb417 and Pb531 were included by sequencing the Exon 2 region of gp43. The pathogenicity was determined by calculating the 50% lethal dose (LD50%) and by counting the number of colony forming units performed in the sixth week post-infection of BALB / c mice. Immunogenicity was determined by the humoral immune response, using the agar gel immunodiffusion reaction and the cellular immunity, determined the concentration of cytokines interleukin-2, interleukin-10, interferonγ, tumor necrosis factor - and factor of vascular endothelial growth in lung tissue. Surgical has been associated with patients with paracoccidioidomycosis, derived from the Botucatu - the Pb234 and Pb417; the Pb326 of a case with a severe severe form; and Pb531, of a case with severe chronic form. The other strains Pb192, Pb01 and 8334 were transferred by the laboratory of Infectious Diseases. Results. Pb417 and Pb326 strains were grouped into the associated strains P. brasiliensis S1a, Pb531 to P. brasiliensis S1b and strains Pb234 and Pb192 to strains deposited as P. restrepiensis (PS3). The results demonstrate the pathogenicity of disease error and severity. The small LD 50 values were measured in the following cases: severe disease, Pb531 and Pb326. Pb531 strain was considered to... (Complete abstract click electronic access below)
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Silva, Muriel Vilela Teodoro. "Avaliação do efeito da expressão do gene da interleucina 32 (IL-32) humana em modelo murino de infecção por Leishmania (Leishmania) amazonensis." Universidade Federal de Goiás, 2016. http://repositorio.bc.ufg.br/tede/handle/tede/6333.
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Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG
IL-32 is a proinflammatory cytokine which has different isoforms. IL-32γ isoform is the most powerful and was detected in lesions of patients with cutaneous leishmaniasis. Murine cells respond to IL-32, however mice lack the gene for this cytokine. To understand the role of IL- 32 in Leishmania (L.) amazonensis, we used transgenic mice for human IL-32γ (IL-32γTg). C57BL/6 mice (WT) and C57BL/6 IL-32γTg were infected with L. amazonensis promastigotes in the ear. The lesion development was followed weekly with a digital caliper (measured in mm of injury). After 3, 6 and 9 weeks, the animals were euthanized for tissue parasitism analysis by the limiting dilution technique, in infected ears, draining lymph node and spleen of mice. The draining lymph node cells were incubated (48 h) in the presence or absence of L. amazonensis antigen (Ag) for analysis of cytokines by ELISA. IL-32γTg mice present IL-32 production in spleen, liver, lymph node and ear. IL-32γTg mice have a lower injury than the WT mice during the third week of infection. From the 5th to the 9th week of infection, the two groups had similar lesion development profiles. Interestingly, in the 3rd week of infection, the parasitic load in the lesion of IL-32γTg mice was 100 times greater than that of WT mice. After three weeks, IL-32γTg mice maintained the same parasitic load up to nine weeks. In WT mice, however, the number of parasites increased exponentially during weeks evaluated. The parasite load in the spleen and lymph node was lower in IL-32γTg mice when compared with WT mice. There was no difference in histological sections of the lesions in WT and IL-32γTg mice infected with L. amazonensis. We did not observe differences between WT and IL-32γTg groups on the product -10) by lymph node cells stimulated with Ag, in the 3rd, 6th and 9th week of infection. Our data suggest that IL-32γ favors infection by L. amazonensis in the early stages, allowing the growth of the parasites. However, this cytokine seems to limit the growth and spread of parasites in the later stages of infection. In vitro analyzes show the similar percentage of infected cells and the number of parasites per infected cell in WT macrophages and IL-32γTg after 3 and 48h of infection with L. amazonensis. However, the production of NO by macrophages seems to be lower in IL- 32γTg mouse cells during infection with L. amazonensis. Understanding the mechanisms by which IL-32γ modulates Leishmania amazonensis infection in mice is essential to define the components that control cutaneous leishmaniasis caused by this specie in humans.
A IL-32 é uma citocina pró-inflamatória que apresenta diferentes isoformas. A isoforma IL- 32γ é a mais potente e foi detectada em lesões de pacientes com leishmaniose tegumentar americana. Células murinas respondem à IL-32, no entanto, camundongos não têm o gene para essa citocina. Para entender o papel da IL-32 na infecção por Leishmania (Leishmania) amazonensis, foram utilizados camundongos transgênicos para a IL-32γ humana (IL-32γTg). Camundongos C57BL/6 (WT) e C57BL/6 IL-32γTg foram infectados com formas promastigotas de L. amazonensis na orelha. O desenvolvimento da lesão foi acompanhado semanalmente com paquímetro digital (medida em mm de lesão). Após 3, 6 e 9 semanas, os animais foram eutanasiados para análise de parasitismo tecidual, pela técnica de diluição limitante, nas orelhas infectadas, no linfonodo drenante e no baço dos camundongos. As células do linfonodo drenante foram incubadas (48 h), na presença ou ausência de antígeno de L. amazonensis (Ag), para análise de citocinas pela técnica de ELISA. Camundongos IL- 32γTg apresentam produção de IL-32 no baço, fígado, linfonodo e orelha. Camundongos IL- 32γTg apresentam uma lesão menor do que a lesão dos camundongos WT, na terceira semana de infecção. Da 5ª até a 9a semana de infecção, os dois grupos apresentaram perfis semelhantes de desenvolvimento da lesão. Curiosamente, na 3ª semana de infecção, a carga parasitária na lesão do camundongo IL-32γTg era 100 vezes maior do que a dos camundongos WT. Após três semanas, os camundongos IL-32γTg mantiveram a mesma carga parasitária até nove semanas. Em camundongos WT, no entanto, o número de parasitos aumentou exponencialmente durante as semanas avaliadas. A carga parasitária do linfonodo e no baço foi menor nos camundongos IL-32γTg, quando comparado com camundongos WT. Não foi observada diferença nos perfis histológicos das lesões nos camundongos WT e IL-32γTg infectados por L. amazonensis. Não foi observada nenhuma diferença entre os grupos WT e IL-32γTg em relação à produção de citocinas (IFNγ, TNFα e IL-10), pelas células dos linfonodos estimuladas com Ag, na 3a, 6a e 9a semana de infecção. Os nossos dados sugerem que a IL-32γ favorece a infecção por L. amazonensis nas fases iniciais, permitindo o crescimento do parasito; no entanto, essa citocina parece limitar o crescimento e a disseminação dos parasitos nas fases mais tardias da infecção. As análises in vitro mostraram porcentagem de células infectadas e número de parasitas por célula infectada semelhantes nos macrófagos dos WT e IL-32γTg com 3 e 48h de infecção por L. amazonensis. Entretanto, a produção de NO por macrófagos parece ser menor nas células de camundongos IL-32γTg durante a infecção por L. amazonensis. Compreender os mecanismos pelos quais a IL-32γ modula a infecção por L. amazonensis nos camundongos é fundamental para a definição dos componentes que controlam a leishmaniose tegumentar causada por esta espécie em seres humanos.
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Zapana, Priscila Rosse Mamani. "Desenvolvimento de um modelo murino para estudo da resposta imune conferida pela proteína do Nucleocapsídeo do vírus Oropouche." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17147/tde-25042018-153023/.
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O vírus Oropouche (OROV) é um arbovírus que ocorre na região amazônica causando surtos de doenças febris agudas e que, ocasionalmente, podem ser associados a meningoencefalite. Aproximadamente 500.000 casos de Oropouche teriam ocorrido no Brasil. Entretanto, não existe vacina contra o OROV. O objetivo deste trabalho foi desenvolver um modelo animal de infecção por OROV para estudar a patogênese da doença e um modelo para testar candidatas vacinais. Protótipo vacinal utilizando a proteína recombinante do nucleocapsídeo (N) de OROV (NrOROV), que é o principal antígeno viral, foi usado como potencial candidato para vacina. Neste estudo utilizou-se um modelo animal em camundongos Balb/c de 12 semanas de idade, inoculados intracerebralmente com 8x105 PFU de OROV, capaz de induzir 100% de letalidade após o terceiro dia da infecção. Altos títulos virais foram encontrados no cérebro e na medula espinhal dos animais. Surpreendentemente, 12 e 24 horas pós-infecção foi possível detectar vírus no fígado e baço (3 Log10 PFU/g) dos camundongos. Com este modelo foram testados os candidatos vacinais. Grupos de camundongos foram imunizados 3 vezes com OROV, OROV e FCA, NrOROV, NrOROV e FCA, NrOROV, Poli I:C e Montanide ISA 720. Após 3 imunizações, os animais foram desafiados com 10 LD50 de OROV e observados por 20 dias. Os animais imunizados com NrOROV e adjuvantes, não foram capazes de produzir anticorpos neutralizantes e adquirir imunidade protetora contra OROV enquanto que os imunizados com OROV apresentaram altos níveis de anticorpos neutralizantes e completa proteção in vivo. Ainda, os anticorpos produzidos pelos animais imunizados permitiram estudar o ciclo de replicação celular do OROV utilizando imunofluorescência.Oropouche (OROV) is an arbovirus that occurs in the South American, Amazon region, producing outbreaks of acute febrile illness occasionally associated to meningoencephalitis. Approximately 500,000 cases of Oropouche have been reported in Brazil in the last 60 years. However, there is no available vaccine for OROV. We show here the development of an animal model of OROV suitable for studies on pathogenesis and vaccine testing. A vaccine prototype based on recombinant OROV nucleocapsid protein (NrOROV), an important viral antigen, was evaluated in the animal model. Initialy, we observed that all 12-week-old Balb/c mice inoculated intracerebrally with 8x105 PFU died after the third day of infection. Surprisingly, OROV genome was detectable in the liver as early as 12 hours post infection (pi) and in the spleen at 24 hours pi at 3 log10 PFU/g. Besides, high viral titers were found in brain and spinal cord. To test the NrOROV as a vaccine candidate, animals divided in 5 groups were immunized subcutaneously 3 times, two weeks apart with either OROV, OROV and Freud complete Adjuvant (FCA), NrOROV, NrOROV and FCA, NrOROV and Poly I:C and Montanide ISA 720. The experiment also included a group of naïve animals. After the third immunization, the animals were challenged with 10LD50 by intracerebral route and followed for 20 days. The animals immunized with NrOROV and adjuvants developed specific antibodies that were not able to neutralize the virus or confer protective immunity against OROV. Nevertheless, mice immunized with OROV showed high levels of neutralizing and protective antibodies. Despite the discouraging results with NrOROV as a vaccine, the mouse model is suitable to study pathogenesis, and to test other vaccines for OROV.
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Koval, Lidia. "Investigating the effect of internal fixation stiffness on metaphyseal fracture healing in a mouse model." Thesis, Queensland University of Technology, 2014. https://eprints.qut.edu.au/75644/1/Lidia_Koval_Thesis.pdf.
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This project examined the differences in healing of metaphyseal bone, when the implants of variable stiffness are used for fracture fixation. This knowledge is important in development of novel orthopaedic implants, used in orthopaedic surgery to stabilise the fractures. Dr Koval used a mouse model to create a fracture, and then assessed its healing with a combination of mechanical testing, microcomputed tomography and histomorphometric examination.
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Zgheib, Sara. "Altérations physiologiques et récupération à long terme dans un modéle murin de séparation associée à une restriction du temps d'accés à l'alimentation : un outil pour l'étude des conséquences de l'anorexie mentale." Thesis, Littoral, 2014. http://www.theses.fr/2014DUNK0428/document.
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L'anorexie mentale (AM) est un trouble du comportement alimentaire qui se caractérise par une recherche obsessionnelle de minceur, une forte réduction de la prise alimentaire et une distorsion de l'image de soi. Elle est associée à de multiples perturbations endocriniennes et métaboliques, et à une altération de la masse et de la microarchitecture osseuses. Les facteurs et les mécanismes qui interviennent dans cette maladie sont très mal connus ce qui limite les options thérapeutiques. Il est donc nécessaire de développer un modèle animal qui reproduise les perturbations physiologiques observées en AM et permette d'étudier les facteurs associés à l'altération osseuse. Dans ce but nous avons développé un modèle murin avec une restriction du temps d'accès à l'alimentation associée à un stress induit par la séparation (separation-based anorexia, SBA). Cette phase SBA de 10 semaines est suivie d'une phase de récupération en conditions standard (REC) de 10 semaines. Chez les souris femelles C57B1/6 en fin de croissance rapide, la phase SBA induit une perte rapide et importante du poids corporel. L'analyse de la composition corporelle par DEXA révèle une diminution rapide de près de 40% de la masse grasse ainsi qu'une baisse progressive de la masse maigre et un arrêt de l'acquisition de la masse osseuse. Au niveau des tibias, la densité minérale cortical et la microarchitecture trabéculaire sont altérées. L'observation des frottis vaginaux et la mesure des ovaires révèlent une perturbation importante des fonctions reproductrices. Les tests de tolérance au glucose ont montré que les souris SBA ont une capacité très élevée à corriger la glycémie. Ces animaux sont fortement hypoleptinémiques, et l'axe GH-IGF-1 est très perturbé. L'étude de l'expression génique de différents tissus adipeux a montré une augmentation du niveau des marqueurs de lipogénèse et de lipolyse, ainsi qu'une forte induction du phénotype "adipocyte brun" dans le tissu adipeux sous-cutané. Après deux semaines de REC, les souris SBA retrouvent très rapidement leur poids corporel, leurs masses maigre et grasse. La masse minérale toujours basse à ce stade est corrigée après 10 semaines de REC, ainsi que la microarchitecture osseuse (étude préliminaire). Tous les autres paramètres étudiés sont normalisés, sauf l'hypoleptinémie qui étonnamment persiste même après 10 semaines de protocol REC et malgré la normalisation de la masse adipeuse. D'après ces résultats, on peut conclure que le modèle SBA reproduit de nombreuses perturbations physiologiques observées en AM. La phase de REC révèle que ces souris ont une importante capacité de récupération. L'hypoleptinémie persistante pourrait favoriser la récupération. L'identification des mécanismes impliqués pourrait fournir des pistes thérapeutiques afin de favoriser la reconstitution du capital osseux des patientes anorexiquesAnorexia nervosa (AN) is an eating disorder mainly developed in adolescent girls and young women. It is characterized by an obsessive search for thinness, a profound undernutrition and a distorted self-image.It is associated with multiple endocrine and metabolic disturbances, decreased bone mass and microarchitectural alteration. Some of the developed adaptations are supposed to be involved in the blockade of the pathologic state. Unfortunately, these adaptations are poorly known and most of them cannot be studied on patients. So it is necessary to develop an animal model which mimics the main consequences observed in human pathology and allows studying the recovery process. For this purpose we adapted a murine model of time restricted feeding associated with chronic stress induced by separation-based anorexia (SBA). C57B1/6 female mice are submitted to a long term SBA protocol (10 weeks) and then a long term phase of recovery (10 weeks). At the beginning of the protocol mice are 8 weeks old, so their fast growth is finishing. SBA protocol induced a rapid and significant loss of body weight. Body composition analysis by DEXA showed a 40% decrease of the fat mass, a progressive loss of lean mass and a blockade of bone mass acquisition. Mice deveoped a high glucose tolerance. The observation of vaginal smears revealed a disruption of the estrous cycle and ovarian histology showed an atrophy of the ovaries. These two alterations suggest a major alteration of reproductive functions. These animals showed a very low leptinemia, and the GH/IGF-1 axis was disrupted. The study of bone alteration by microtomography indicated an alteration of bone microarchitecture and of cortical bone mass, mimicking osteoporosis often described in AN patients. Body weight, lean and fat masses were normalized quickly during the REC protocol. Bone mineral content still low after 2 weeks of REC protocol was fully corrected after 10 weeks. The estrous cycle ovarian size and the GH/IGF-I were normalized. Surprisingly, hypoleptinemia persisted even after 10 weeks of REC and despite the normalization of the fat mass. This result has been confirmed by the low level of leptin gene expression in various adipose tissues. Finally, the SBA protocol is valuable model of AN because numerous physiological alterations described in AN are mimicked in this model. The recovery phase revealed the high capacity of mice to normalize the long term alterations. Persitent hypoleptinemia could contribute to the normalization of body composition. However, the balance between central and peripheral effects of the uncorrected hypoleptinemia remains to be determined. This persisting hypoleptinemia could be used for the revision of the therapeutic strategies aiming to correct AN-induced osteoporosis
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Johansson, Ann-Sofie. "Establishment and characterization of a murine T-cell lymphoma/leukemia model." Doctoral thesis, Umeå universitet, Institutionen för strålningsvetenskaper, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-35195.
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Mouse models of human disease are valuable tools for studying pathogenesis and for evaluating novel therapies. T-cell lymphoma is a relatively rare disease in humans, affecting 100-150 persons yearly in Sweden. It exists in both aggressive and more indolent forms. We have established a mouse model for an aggressive T-cell lymphoma, the T-cell lymphoma/leukemia (TLL) mouse. In the present thesis, the TLL mouse model was characterized and used for experimental therapeutic and primary prevention studies. The TLL mouse was established unintentionally in our laboratory during work on VH-gene replacement in a “knock-in” mouse experimental setting. The generated chimeras all developed aggressive T-cell lymphomas affecting the lymphoid organs, lungs, kidneys and liver. The lymphoma phenotype segregated from the targeted locus and we could demonstrate the presence of Moloney murine leukemia virus (MMLV) in the germline of the affected mice. MMLV is a retrovirus known to induce T-cell lymphomas when inoculated in newborn mice. We further characterized two TLL substrains; TLL-2 and TLL-14 carrying the proviral integrations on chromosomes 2 and 14 respectively. Significant differences were found between the substrains regarding lymphoma frequency and immunophenotype, the TLL-14 substrain developing tumors with higher frequency than TLL-2 and with a more mature immunophenotype. A transfer model was developed in which TLL cells could be readily transferred intravenously to syngenic recipients causing aggressive lymphomas. The transfer model was used in a therapeutic study where the selective COX-2 inhibitor celecoxib was evaluated as a single agent and in combination with the established anti-tumor agent cyclophosphamide. The study was based on results from other tumor types that have indicated celecoxib, originally an anti-inflammatory and analgetic drug, to have possible anti-tumor effects. In our TLL model, however, we could not demonstrate any benefit of celecoxib monotherapy or any additive effect to cyclophosphamide. Dietary fatty acids, in particular omega-3 fatty acids, have been a focus of public and scientific interest due to observed effects on the prevention of cardiovascular disease, cancer and inflammatory conditions. In addition, omega-3 fatty acids inhibit T-cell proliferation in vitro. We supplemented the diet of TLL mice with omega-3 and omega-6 fatty acids respectively and could demonstrate a significant delay in lymphoma onset between 5-8 months of age in the group receiving an omega-3 rich diet.
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Kus, Agnieszka. "Neoadjuvant Oncolytic Virus Therapy in a Murine Model of Cancer Surgery." Thesis, University of Ottawa (Canada), 2010. http://hdl.handle.net/10393/28847.
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Surgery is the primary treatment modality for most solid tumours. Despite complete resection, the development of metastatic disease limits it curative potential and provides the rationale for neoadjuvant (preoperative) therapies. Oncolytic Viruses (OVs) are replicating therapeutics that are selected or engineered to grow in malignant cell types and are capable of killing the infected target cell, while leaving normal, adjacent cells unharmed. OVs may be an ideal candidate for generating a potent anti-tumour immune response due to effective recruitment of immune cells into the tumour microenvironment, proper activation of immune cells, and generation of tumour antigen-specific T cells. Preoperative OV therapy may serve as a neoadjuvant immunotherapy capable of preventing the development of metastatic disease by generating an effective immune response. Although VSVDelta51GM-CSF treatment of CT26lacZ tumours is able to generate an anti-tumour immune response capable of preventing the growth of a subsequent CT26lacZ tumour, preoperative VSVDelta51GM-CSF treatment of primary tumours in a CT26lacZ surgery model was unable to generate an immune response capable of rejecting a secondary tumour. This abrogation of protection against the secondary CT26lacZ tumour was observed to be a result of the surgical intervention. Preoperative VSVDelta51GM-CSF and VSVDelta51 treatment IV of primary tumours in a B16-F10 surgery model was unable to generate an immune response capable of reducing the number of secondary surface lung metastases. JXS94mGMCSF treatment IT of a primary tumour in a B16-F10 surgery model was able to reduce the number of secondary surface lung metastases, while JXS94mGMCSF injected IV was not. This suggests that one of the factors in the induction of an anti-tumour immune response by neoadjuvant therapy in a surgical model may be the route of administration of ov.
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Sun, Guoxian. "A murine cell model for karyotype instability in chronic myelogenous leukemia." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=26154.
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Chronic myelogenous leukemia (CML) is a neoplastic disorder of pluripotent hematopoietic stem cells which follows a biphasic clinical course consisting initially of a relatively benign chronic phase followed by progression to a fatal acute leukemia (CML blast crisis). A clonal cytogenetic abnormality (i.e. the Philadelphia or Ph chromosome), resulting from the reciprocal translocation t(9;22)(q34;q11), is found in over 95% of patients. A hybrid gene is created at the breakpoint of Ph, derived from the ABL proto-oncogene (9q34) and from the BCR gene (22q11), which results in the expression of a 210 KDa fusion protein tyrosine kinase called P210BCR/ABL (P210). Expression of P210 alone is generally believed to be sufficient to induce chronic phase CML but, the deregulation of additional genes appears to be required for progression to CML blast crisis, as inferred by the presence of secondary cytogenetic abnormalities in over 80% of patients. To investigate the potential significance of P210 expression in the induction of genetic instability associated with CML progression, I studied cytogenetic changes in a murine cell line (32D) which expressed P210BCR/ABL from a retroviral vector. Using Giemsa-trypsin banding technique, I found a common marker chromosome t(4;12) in 13 subclones, a second new marker t(2;17) in 3/13 subclones and, additional clonal marker chromosomes in all of the subclones examined. Six subclones consisted of two or three karyotypically distinct cell populations. This study demonstrates that BCR/ABL can directly induce both numerical and structural chromosomal abnormalities in hematopoietic cells. This murine cell model may provide a useful tool to further study the causal relationship of cytogenetic instability and cooperative molecular events involved in the initiation and progression of CML.
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Nundlall, Seema. "The pathomolecular mechanisms in a murine model of multiple epiphyseal dysplasia." Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492857.
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Multiple epiphyseal dysplasia (MED) is characterized by dwarfism and early-onset osteoarthritis and can result from mutations in the gene encoding matrilin-3 (MATN3). To determine the precise disease mechanisms that underpin the pathophysiology of MED, a knock-in murine model of MED has recently been generated with the disease-causing matn3: V194D mutation. Mice that are homozygous for the mutation (MM) are normal at birth but develop a progressive dysplasia that is characterized by the intracellular retention of mutant matrilin-3. The mutant mice also display a significant decrease in chondrocyte proliferation and dysregulated apoptosis by 3 weeks of age.
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Dukaczewska, Agata Katarzyna [Verfasser]. "Establishment of a murine model of ocular toxoplasmosis / Agata Katarzyna Dukaczewska." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2012. http://d-nb.info/1029849536/34.
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Lopes, de Souza Roberto. "A novel model for non-invasive loading of the murine tibia." Thesis, Royal Veterinary College (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.425714.
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Pitchford, Simon Charles. "The role of platelets in a murine model of allergic inflammation." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397780.
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Corsino, Betsy Ann 1962. "THE PULMONARY RESPONSE INDUCED BY GLASS FIBERS (INFLAMMATION, SILICOSIS, MURINE MODEL)." Thesis, The University of Arizona, 1986. http://hdl.handle.net/10150/291468.
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Williams, Jessica. "Characterisation of vascular dysfunction in a murine model of rheumatoid arthritis." Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/99760/.
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Background RA patients have an increased prevalence of CVD independently of traditional risk factors. Studies using a mouse model of inflammatory arthritis – mCIA have shown decreased vascular constriction response of the thoracic aorta to 5HT, associated with increased MMP-9 production. The source of the latter, inflammatory content and impact on the structural proteins of the vessel wall remains elusive. Methods Myography was used to determine vascular constriction response in mCIA animals. Immunohistochemistry determined presence of F4/80+ macrophages, Ly6G+ neutrophils, DR3 and MMP-9. DR3 was assessed in the healthy and arthritic constriction response using DR3-/- and DR3WTs. Vascular calcification was determined in short and long term mCIA using RT-qPCR. Protein levels were quantified using immunohistochemistry. Collagen and elastin were determined using Van Geisson and Ver Hoeffs staining. The role of the AIM2 inflammasome in mCIA associated vascular dysfunction was also determined using CRID3 therapy. Results Increased macrophages with complimentary DR3 staining were observed in the aorta and PVAT.DR3-/- had normal constriction response despite increased cells and MMP-9 in the PVAT. DR3 ablation decreased arthritis onset and severity, however, worsened the vascular function. DR3 PVAT was protective to the constriction response. Calcification mediators remained constant following the onset of mCIA. Long term mCIA showed exciting trends of increase to calcification mediators. Collagen and elastin both become deregulated during mCIA and showed a fibrosis like phenotype. Blocking the AIM2 inflammasome had no impact on mCIA onset but partially restored vascular constriction response. Discussion Systemic inflammation is key in explaining the vascular dysfunction associated with the mCIA model. mCIA allows us to determine very early changes in the vasculature associated with systemic inflammation as opposed to long term changes. Macrophages specifically are early inflammatory cells implicated in the aorta and are associated with both DR3 and AIM2, suggesting them as key players contributing to vascular dysfunction in this model. Successful AIM2 blocking therapy has potential to be used in human RA patients to reduce CV co-morbidity.
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Chan, Derek Steven Hung Che. "Tumoral immune privilege in a murine model of pancreatic ductal adenocarcinoma." Thesis, University of Cambridge, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709503.
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Ono, Sachiko. "Local inflammation exacerbates cutaneous manifestations in a murine autoimmune pemphigus model." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225507.
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Thor, Larsen Søren. "Adjuvant effect of phthalates and monophthalates in a murine injection model /." Cph. : Department of Pharmacology, Royal Danish School of Pharmacy and Department of Chemical Working environments, National Institute of Occupational Health, 2002. http://www.dfh.dk/phd/defences/Soeren%20Thor%20Larsen.html.
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Lukefahr, Ashley Leigh. "CHARACTERIZING BONE LOSS IN AN OVARY-INTACT MURINE MODEL OF MENOPAUSE." Thesis, The University of Arizona, 2009. http://hdl.handle.net/10150/192319.
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Gliddon, Briony Lee. "Enzyme replacement therapy in a murine model of mucopolysaccharidosis type IIIA /." Title page, contents and abstract only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09phg5595.pdf.
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Palma, Luana Carneiro. "Doença esteatóica não alcoólica do fígado: comparação das alterações histológicas hepáticas entre modelo murino e pacientes obesos." Centro de Pesquisas Gonçalo Moniz, 2013. https://www.arca.fiocruz.br/handle/icict/7149.
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Luana Palma. Doença esteatotica...2012.pdf: 6491139 bytes, checksum: 17714fa9ab206495fbf5e1aa05890deb (MD5)Made available in DSpace on 2013-10-15T15:33:27Z (GMT). No. of bitstreams: 1 Luana Palma. Doença esteatotica...2012.pdf: 6491139 bytes, checksum: 17714fa9ab206495fbf5e1aa05890deb (MD5) Previous issue date: 2013
Universidade Federal da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
A Doença Esteatótica Não Alcoólica do Fígado (do inglês Nonalcoholic Fatty Liver Disease – NAFLD) é uma doença crônica hepática de caráter espectral, que vai desde a esteatose simples até a esteato-hepatite não alcoólica. A progressão para cirrose e carcinoma hepatocelular têm sido descrita. A NAFLD apresenta aspectos histológicos semelhantes à doença hepática relacionada ao álcool (esteatose, inflamação lobular, corpúsculos de Mallory e fibrose), mas acomete indivíduos com história negativa de consumo excessivo de álcool. A NAFLD é uma das principais doenças crônicas hepáticas mundiais, e os indivíduos obesos representam a maioria dos casos da doença. Os mecanismos envolvidos na progressão da esteatose para esteato-hepatite não são bem compreendidos. Neste aspecto, modelos murinos da NAFLD têm sido frequentemente utilizados para elucidação destes mecanismos. A maioria dos modelos disponíveis é resultante de modificações genéticas e/ou nutricionais e, em geral, não simulam as alterações metabólicas e histológicas comumente vistas em pacientes com NAFLD. Em nosso grupo, foi proposto um novo modelo de NAFLD. Camundongos C57BL/6 alimentados com dieta rica em gordura (High Fat - HF) demonstraram alterações metabólicas e histológicas sugestivas de NAFLD. O objetivo do presente trabalho foi comparar alterações histológicas hepáticas presentes nestes camundongos com as alterações observadas em pacientes obesos. Amostras de fígados de pacientes obesos e de camundongos alimentados com a dieta HF foram utilizadas. Os tecidos hepáticos foram corados em Hematoxilina & Eosina e Picrossírius Red para avaliação das alterações hepáticas (esteatose, balonização, inflamação, corpúsculos de Mallory-Denk e fibrose). Além disso, foi realizada imunoistoquímica para avaliação da presença de células estrelares ativadas e de células progenitoras hepáticas, células envolvidas na fibrose e no desenvolvimento de carcinoma hepatocelular, respectivamente. Os resultados demonstraram que os fígados de todos os pacientes obesos exibiram esteatose macrovacuolar, balonização hepatocelular, inflamação lobular e fibrose perissinusoidal, o que caracterizou estes pacientes como portadores da NAFLD. As mesmas alterações foram observadas em fígados de camundongos alimentados com a dieta HF. As células estrelares ativadas foram observadas em todos os pacientes obesos, assim como em camundongos de dieta HF. As células progenitoras hepáticas foram observadas na maioria dos pacientes obesos. O fígado de todos os camundongos alimentados com dieta HF exibiram células progenitoras hepáticas. A partir dos dados obtidos, pode-se concluir que fígados de camundongos alimentados com dieta HF exibem alterações histológicas hepáticas similares às observadas em pacientes obesos. Isto abre perspectivas para a utilização do modelo proposto em estudos que busquem elucidar os mecanismos envolvidos na patogênese da NAFLD.
Nonalcoholic Fatty Liver Disease (NAFLD) is a chronic liver disease ranging from simple steatosis to nonalcoholic steatohepatitis. The progression to cirrhosis and hepatocellular carcinoma has been reported. The NAFLD shows histological features similar to alcohol-related liver disease (steatosis, lobular inflammation, fibrosis and Mallory-Denk bodies), but affects individuals with no history of excessive alcohol consumption. The NAFLD is a major chronic hepatic disease in the world, and obese individuals represent the majority of cases of the disease. The mechanisms involved in the progression of steatosis to steatohepatitis are not well understood. In this regard, murine models of NAFLD have been frequently used for elucidation of these mechanisms. Most available models are the result of genetic or nutritional modifications, and generally do not mimic metabolic and histologic changes commonly seen in patients with NAFLD. In our group, we have proposed a new model of NAFLD. Mice fed high fat diet (HF diet) demonstrated metabolic and histological features suggestive of NAFLD. The aim of this study was to compare liver histological alterations present in these mice with the changes observed in obese patients. Samples of livers of obese patients and mice fed HF diet were used. For assessment of liver alterations, such as steatosis, ballooning, inflammation, Mallory- Denk bodies and fibrosis, tissues were stained with hematoxylin & eosin and picrossirius red. In addition, the presence of activated stellate and progenitor liver cells was estimated using immunohistochemistry. The results show that the livers of all obese patients exhibited macrovesicular steatosis, hepatocellular ballooning, perisinusoidal fibrosis, and lobular inflammation, which characterized these patients with NAFLD. Similar changes were observed in livers of mice that fed the HF diet. Activated stellate cells were observed in all obese patients as well as in mice HF. Hepatic progenitor cells were observed in most obese patients. The liver of all animals fed the HF diet exhibited liver progenitor cells. From the data obtained, it can be concluded that livers of mice fed with HF diet exhibit liver abnormalities similar to those observed in obese patients. This opens perspectives for the use of the proposed model in studies that seek to elucidate the mechanisms involved in the pathogenesis of NAFLD.
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Dobry, Allison S. "Utilizing a Novel Giant Congenital Melanocytic Nevus Murine Model to Investigate Therapeutic Strategies and Model Tumorigenesis." Thesis, Harvard University, 2017. http://nrs.harvard.edu/urn-3:HUL.InstRepos:32676136.
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Giant congenital melanocytic nevi (gCMN) are oncogene-driven proliferations of melanocytes present since birth that are greater than 20 cm in projected adult size, and have a melanoma conversion frequency of ranging from 5-15%. Patients with gCMN typically develop melanoma in early childhood that is extremely aggressive and almost universally fatal. Therefore, targeted therapies to induce nevus regression would be enormously beneficial. NRAS activating mutations are postulated to be the driver mutation gCMN. Described here are two novel gCMN preclinical murine models that harbor an NrasQ61R mutation. Evaluation of both the constitutive nevus model (Dct promoter-driven constitutive Cre with NrasQ61R mutation) and the inducible nevus model (Tyr promoter-driven tamoxifen-inducible CreERT2 with NrasQ61R mutation) demonstrate that both models recapitulate human gCMN histological architecture and model spontaneous tumorigenesis. Of the various drug candidates tested, topical administration of a combination of the MEK inhibitor binimetinib and the c-KIT inhibitor imatinib was superior in causing almost complete nevus regression, as measured by a reduction of melanin deposition and melanocytes in the dermal layer. This may represent a potential topical treatment strategy for the regression of gCMN that avoids both the more deleterious side effects of either systemic drug administration or large-scale surgical procedures. Ultimately, this preclinical murine model may help generate new information about the rare, but deadly gCMN that may aid in improving daily symptoms from these lesions as well as hopefully reduce overall melanoma risk.
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Garbe, Annette. "Immune responses against spontaneous tumors in a murine model for pancreatic adenocarcinoma." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972598359.
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Kassis, Elias Noah. "Nanoparticle use in the modulation of transplant rejection in a murine model." Yale University, 2010. http://ymtdl.med.yale.edu/theses/available/etd-03052010-124710/.
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Solid organ transplant has emerged over the last half century as an important treatment for solid organ failure. Management has matured dramatically over the past two decades with improvements in acute rejection, but long-term graft survival has improved very little and current treatment is limited by the side-effects and toxicities of immunosuppressive medications. Nanoparticle delivery of therapeutics, improving transport characteristics and decreasing systemic and local toxicity has emerged as a dynamic treatment modality, but little work has been done using nanoparticles in transplantation. Our research examined the use of CD4-targeted nanoparticles encapsulated with mycophenolic acid (MPA), a commonly used immunosuppressant in organ transplantation. This work is the first to examine antigen-specific targeting of nanoparticles in any transplant model. MPA-loaded particles show a slow and continuous release profile and biodistribution suggested retention in the spleen. Targeting of nanoparticles to CD4 T cells was suggested using ex vivo and in vitro flow cytometry. In the fully allogeneic MHCII mismatch BALB/C to C57BL/6 mice we found improved graft survival in the non-targeted MPA group and even greater graft survival in the CD4-targeted group. Targeted and non-targeted particle groups showed equal delay in rejection in the less immunogenic single MHC mismatch B6.H-2bm12 to C57BL/6 model that we showed to be CD4 dependent. In both models, graft survival times were increased over free drug and controls with roughly one thousand fold lower dose of drug in the nanoparticles as compared with free MPA. Consistent with these findings were decreased proliferation with targeted and non-targeted MPA-nanoparticles using in vitro and ex vivo mixed lymphocyte reactions. We postulated that the similar rejection times in targeted and non-targeted groups was due to dendritic cell (DC) involvement and we found active uptake of nanoparticles in DCs, a decrease in inflammatory cytokine production and a decrease in treated DCs ability to stimulate T cells via mixed lymphocyte reactions. Furthermore we found a possible mechanism in the DC interaction with T cells through the upregulation of the inhibiting co-stimulatory molecules B7-DC and B7-H1 on DCs treated with MPA-nanoparticles. We also found possible upregulation of CD4+CD25+ Foxp3 expressing Tregs which may serve to increase graft acceptance. These results explore the involvement of dendritic cells in the process of nanoparticle-induced graft acceptance and suggest the feasibility of using nanoparticle drug vectors in clinical transplant.
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Hsu, Chiao-Wen Ivy. "Serpina3n accelerates wound closure in a murine model of diabetic wound healing." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/50361.
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Chronic, non-healing wounds are a major complication of diabetes and are characterized by chronic inflammation and excessive protease activity. While once thought to function primarily as a pro-apoptotic serine protease, granzyme B (GzmB) can also accumulate in the extracellular matrix during chronic inflammation and cleave extracellular matrix (ECM) proteins that are essential for proper wound healing, including fibronectin. We hypothesized that GzmB contributes to the pathogenesis of impaired diabetic wound healing through excessive degradation of the ECM. In the first part of the thesis, we demonstrated that the majority of GzmB was secreted by mast cells and localized in the wound edges and granulation tissues of completely reepithelialized diabetic mouse wounds at higher levels. Subsequently, we observed that GzmB induced detachment of mouse embryonic fibroblasts and also showed that co-incubation with a mouse serine protease inhibitor, serpina3n (SA3N), abrogated this effect. Finally, we administered SA3N to diabetic mouse wounds and found that wound closure including both reepithelialization and contraction were significantly increased in wounds treated with SA3N. Histological and immunohistochemical analyses of the SA3N-treated wounds revealed a more mature, proliferative granulation tissue phenotype as indicated by increased cells with proliferative activity, vascularization, contractile myofibroblasts, as well as collagen deposition in remodeling tissues. Skin homogenates from SA3N-treated wounds also exhibited greater levels of full-length intact fibronectin when compared to control wounds. In summary, our findings suggested that GzmB contributes to the pathogenesis of diabetic wound healing through the proteolytic cleavage of fibronectin that are essential for normal wound closure, and that inhibition of GzmB can promote granulation tissue maturation and collagen deposition. These results offer preliminary evidence that a GzmB inhibitor may be a relevant therapeutic target in wound management therapy.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate