Browsing by Subject "Mice"
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Item Evaluation of the Light Emission Kinetics in Luciferin/Luciferase-Based In Vivo Bioluminescence Imaging for Guidance in the Development of Small Animal Imaging Study Design(2006-05-15) Bollinger, Robert Albin; Mason, Ralph P.Bioluminescence imaging (BLI) is gaining acceptance as a small animal imaging modality useful for visualizing cellular and molecular activity in vivo, and especially for evaluating tumor development and efficacies of treatments. Various studies have validated the technique for a number of purposes, including the quantification of tumor burden; however, many basic questions have not been investigated whose answers may ultimately impact the conclusions drawn from the results. Primarily, consideration of the impact of BLI emission kinetics has not been rigorously addressed. This study provides information on the effects of different routes of luciferin substrate injection on the BLI kinetic profile, including time to peak emission, magnitude of peak emission, and emission decay characteristics. This study also presents for the first time the use of subcutaneous (s.c.) luciferin injection and the use of s.c. luciferin injection followed by continuous s.c. infusion (s.c.i.) for establishment of stable BLI light emission. Further, results are presented of the kinetic profile changes associated with 1) inhaled and injected anesthesia; and 2) ambient air heating on mouse core temperature. The study demonstrated substantial differences in the peak light emission with i.v. providing the highest, with s.c., s.c.i. and i.p yielding 30% or less of the light emission of the i.v. route. The correlations between tumor burden and BLI light emission were moderately strong (R>0.75) for each administration route, but at varying times following injection, providing information for establishment of optimal image start times. Surprisingly, ambient cooling of the animal while under anesthesia yielded peak light emissions of up to 100% higher than those obtained when ambient air heating was used to maintain mouse core temperature. Finally, guidelines are presented to aid investigators in development of BLI study design to give due consideration to luciferin administration routes, anesthesia protocol, and animal temperature maintenance.Item Loss of Ventromedial Hypothalamic Leptin Receptors Results in Increased Adiposity and a Metabolic Syndrome(2008-05-12) Bingham, Nathan Christian; Parker, Keith L.Obesity is a leading health problem here in the United States and in other developing countries. Obesity is a risk factor for several life-threatening conditions including Type II diabetes, hypertension, and cardiovascular disease. Given the growing obesity epidemic, understanding the mechanisms whereby the central nervous system monitors and regulates energy homeostasis has become a major focus of scientific research in the last several decades. The discovery that mice fed a low fat diet exhibit significantly increased adipose mass with no difference in weight compared to wild-type littermates. Further, these mice exhibit a metabolic syndrome including mild steatosis, dyslipidemia, and hyperleptinemia. From a young age, Lepr KOleptin, an adipocyte-derived hormone, acts on the brain to suppress appetite and stimulate energy expenditure greatly extended our understanding of such mechanisms. The leptin receptor is expressed in a number of hypothalamic nuclei known to play a role in energy homeostasis. While much work has focused on leptin's actions in the arcuate nucleus, other sites have received substantially less attention. Here, I report that mice lacking leptin receptors within the ventromedial hypothalamic nucleus (Lepr KOVMH) develop increased adiposity and a metabolic syndrome. Lepr KOVMH mice fed high fat rodent chow show an increased sensitivity to diet-induced obesity, while Lepr KOVMH mice are hyperinsulinemic and eventually become glucose intolerant. These data demonstrate that Lepr KOVMH mice are a novel genetic model of obesity and may be used for the study of energy partitioning, lipogenesis, and central leptin signaling.Item Mucosal HIV-1 Transmission in Humanized Mice(2008-05-13) Denton, Paul Wesley; Garcia-Martinez, J. VictorHIV-1 infects ~6,800 people each and every day, transmitting predominantly through unprotected sexual contact. On a global scale, vaginal transmission now accounts for more than half of newly acquired HIV-1 infections. In developed countries intrarectal infection represents a major form of HIV-1 transmission. The social and economic toll of this disease has created an urgency to develop and implement novel approaches capable of preventing HIV-1 transmission. Yet this process has been hindered by the lack of adequate small animal models for pre-clinical efficacy and safety testing. Given the importance of mucosal HIV-1 transmission, the susceptibility of humanized mice to intrarectal and intravaginal HIV-1 infection was investigated. Human lymphocytes, including CD4+ T cells, generated in situ from hematopoietic stem cells reconstitute the gastrointestinal tract and the female reproductive tract of Bone marrow Liver Thymus (BLT) mice. The presence of human CD4+ T cells in these mucosal tissues renders BLT mice susceptible to both intrarectal and intravaginal HIV-1 transmission. Mucosally transmitted HIV-1 disseminates systemically in BLT mice. Effects of disseminated HIV-1 infection include a systemic loss of CD4+ T cells, particularly in gut associated lymphoid tissue, which closely mimics what happens in HIV-1 patients. The utility of humanized mice to study mucosal HIV-1 transmission is particularly highlighted by the demonstration herein that pre-exposure prophylaxis with antiretroviral drugs can prevent intravaginal HIV-1 transmission. This experimental finding has important implications for the clinical implementation of antiretroviral-based pre-exposure prophylactic measures to prevent the spread of AIDS. The goal of this dissertation project was to determine the suitability of the BLT mouse to serve as an animal model of HIV-1 transmission and as a model for assessing interventions aimed at preventing HIV-1 transmission. My conclusions are that BLT mice are susceptible to both intrarectal and intravaginal HIV-1 transmission and that pre-exposure prophylaxis with FDA approved antiretroviral drugs does prevent vaginal transmission in BLT mice. Thus, the BLT mouse system is an excellent candidate for pre-clinical evaluation of both microbicides and pre-exposure prophylactic regimens to prevent mucosal HIV-1 transmission.Item Narrowing of the SLES1 Internal Reveals Complex Epistatic Interactions in the Suppression of Autoimmunity(2010-05-14) Belobrajdic, Katherine Ann; Wakeland, Edward K.Sle1 is a potent susceptibility locus for spontaneous systemic autoimmunity derived from the NZM2410 mouse strain. The NZW-derived suppressive modifier locus, Sles1, specifically prevents the spontaneous loss in tolerance mediated by the B6.Sle1 congenic. Sles1 had previously been fine-mapped to a remarkably gene-rich region on murine chromosome 17 containing nearly 70 genes. A series of mouse strains were constructed with a variety of suppressive and non-suppressive variants of Sles1 on the B6.Sle1 genomic background which have revealed multiple layers of epistatic gene interactions within the Sles1 interval. Phenotyping of a truncated recombinant interval mapped the Sles1 phenotype to an approximately 638 KB segment, which combined with genomic and expression analysis, suggested Btnl2 and the H2 genes are strong candidates for Sles1. Finally, further characterization of the Sles1 interval has revealed an allele-specific and tissue-specific reduction of major histocompatibility complex (MHC) Class II molecules on the surface of B cells, as well as a possible role for follicular helper T cells in the development of Sle1-mediated autoimmunity. Understanding how Sles1 and other modifiers suppress systemic autoimmunity will reveal important insights for developing therapeutic strategies for systemic lupus eythematosus (SLE).Item [News](1982-02-05) Willding, LizItem Number 6 has the cure for cancer... : any cancer(2008-04-11) Yarbrough, W. C.Item Origin and Function of CD8 T Cells in MHC Class Ia-Deficient Mice(2005-12-20) Su, Jie; Forman, JamesB6.H-2Kb-/-Db-/- (DKO) mice are devoid of class Ia but express normal levels of class Ib molecules. They have low levels of CD8 T cells in both the thymus as well as peripheral T cell compartments. Although the percentage of splenic CD8αα T cells is increased in these animals, approximately 90% of CD8 T cells are CD8αβTCRαβ. In contrast to B6 animals, most of the CD8 T cells from these mice have a memory phenotype (CD44hi) including both CD8αβ and CD8αα subsets. In the thymus of DKO animals, there is a decrease in the percentage of single positive CD8 T cells, although most are CD44low, similar to that seen in B6 mice. Our results indicated that the paucity of CD8 T cells in DKO mice might be in part due in reduced thymic export, lower basal proliferation, high apoptosis, and inability to undergo homeostatic expansion. DKO mice have greatly reduced numbers of mature CD8αβ T cells in their periphery. However, these non class Ia selected CD8αβ cells are able to mediate immune responses to a number of pathogens. Approximately 60% of the CD8αβ T cells in the spleen and peripheral lymph nodes of naïve DKO mice display a memory (CD44hi) phenotype. To investigate the origins of these non class Ia selected CD8αβCD44hi cells, we traced the phenotype of recent thymic emigrants (RTEs) and found that most were CD44lo. We also determined if their appearance was thymusdependent and found that only a small percentage of non class Ia selected CD8αβCD44hi cells develop in a thymus-independent pathway. Functionally, CD8αβCD44hi cells from DKO mice are able to secrete IFN-γ in response to interleukin (IL)-12 and IL-18 in the absence of cognate antigen. When challenged with anti-CD3 in vivo, nearly half of these cells produce IFN-γ within 3 hours. When purified CD8αβCD44hi cells from Thy1.2.DKO mice were transferred into Thy1.1 DKO recipients and then challenged with Listeria monocytogenes (LM), an antigen specific anti-LM response was observed six days later. Our data suggest that non class Ia selected CD8αβCD44hi cells in naïve animals can respond to antigen and play a role in the innate as well as the early phase of the acquired immune response.Item The Role of Class I Histone Deacetylases in Cardiovascular Development and Disease(2008-05-13) Montgomery, Rusty Lee; Olson, Eric N.Histone acetylation/deacetylation is a dynamic process that coordinates proper gene expression through the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibitors continue to show promise in a multitude of pathological settings such as cancer and heart disease, however the role of individual HDACs remains largely unexplored. Genetic studies have shown class II HDACs regulate developmental and physiological processes through the interaction with and repression of myocyte enhancer factor 2, MEF2, however the biological functions of class I HDACs have not been determined. To potentially understand the role of individual class I HDACs in development and disease, we generated conditional knockout alleles for HDAC1, HDAC2, and HDAC3. Through global and tissue specific analyses, we hope to identify specific roles of these enzymes in developmental, physiological, and pathological settings. Here I show that HDAC1 and HDAC2 act redundantly in controlling cardiac growth, morphogenesis, and contractility. Mice with cardiac-specific deletion of either HDAC1 or HDAC2 are viable and lack obvious phenotypes, however cardiac-specific deletion of both HDAC1 and HDAC2 results in lethality by two weeks of age. These mice show cardiac arrhythmias, dilated cardiomyopathy, and increased expression of calcium channels and skeletal muscle-specific contractile proteins. HDAC3 is an independent regulator of cardiac development. Global deletion of HDAC3 results in embryonic lethality, whereas cardiac-specific deletion of HDAC3 results in massive cardiac hypertrophy by 3 months of age and lethality by 16 weeks. These mice show metabolic abnormalities including up-regulation of genes involved in fatty acid uptake and oxidation, down-regulation of the glucose utilization pathway, and ligand induced myocardial lipid accumulation. Additionally, these hearts show mitochondrial dysfunction and decreased cardiac efficiency. These studies have identified HDAC3 as a central regulator of myocardial energy metabolism. In addition to cardiac studies, tissue-specific deletions in multiple cell-types have led to the discovery that functional redundancy of HDAC1 and HDAC2 is not restricted to postnatal cardiomyocytes, but extends to early cardiomyocytes, endothelial cells, smooth muscle cells, chondrocytes, and neurons. Deletion of HDAC1 or HDAC2 individually in these cell types does not evoke a phenotype, however deletion of both HDAC1 and HDAC2 results in embryonic lethality or neonatal lethality. Taken together, these studies identify HDAC1 and HDAC2 as redundant regulators of multiple cell types during development. Collectively, these studies have identified distinct and specific roles for HDAC1, HDAC2, and HDAC3 during development and disease. Furthermore, these genetic studies have provided mechanistic insight into the pathways regulated by each enzyme. Additional analyses on these mice will prove instrumental to the development of more specific inhibitors for the treatment of a wide array of pathological conditions.Item [Southwestern News](2002-09-20) Carter, WayneItem [Southwestern News](1999-08-31) Steeves, Susan A.Item [Southwestern News](2007-05-27) McKenzie, AlineItem [Southwestern News](1999-07-09) Steeves, Susan A.Item [Southwestern News](1999-08-06) Steeves, Susan A.Item [UT Southwestern Medical Center News](2006-02-09) McKenzie, AlineItem [UT Southwestern Medical Center News](2007-06-05) Despres, CliffItem [UT Southwestern Medical Center News](2006-05-03) McKenzie, AlineItem [UT Southwestern Medical Center News](2008-05-20) McKenzie, AlineItem [UT Southwestern Medical Center News](2006-01-18) McKenzie, AlineItem [UT Southwestern Medical Center News](2006-10-22) Despres, Cliff