This dissertation project was aimed at elucidating cellular and molecular responses to myocardial infarction. Our work identified canonical wnt signaling as a molecular pathway that is induced in the healing (granulation tissue formation) stages of myocardial infarction (MI). We identified endothelial-to-mesenchymal transition as a cellular response to MI that occurs during granulation tissue formation, coincident with canonical wnt activation. We show that canonical wnt signaling is sufficient to induce endothelial-to-mesenchymal transition in the mature vasculature. Our findings suggest that canonical wnt signaling mediates endothelial-to-mesenchymal transition to generate new blood vessels and scar-forming myofibroblasts during post-infarction granulation tissue formation. These findings suggest an intricate cellular (EndMT) and molecular (canonical wnt signaling) connection between two critical repair mechanisms with apparently opposing effects, beneficial neovascularization and detrimental fibrosis. This intrinsic link may open the opportunity to improve the course of cardiac repair post-MI by temporal and cell type-specific manipulation of canonical wnt signaling. Approved: Professor Antonis Hatzopoulos Date: 09-02-2010

This project is concerned with understanding the role of the mRNA-binding protein Nab2 in the process of nuclear mRNA export. In this dissertation I characterize changes that occur to Nab2s structure and localization during cellular response to increased growth temperatures, known as the heat shock response. I show that Nab2 is both phosphorylated by the MAP kinase Slt2, and re-localizes to discrete intranuclear foci during heat shock. Further, I show that these changes are involved in nuclear retention of mRNA during heat shock, and that loss of the Nab2 kinase results in lack of this retention. In summary, this work demonstrates that Nab2, and the MAP kinase Slt2, are involved in nuclear retention of mRNA during heat shock.

The mesodermal germ layer contributes many cell types that comprise the coelomic organs during embryogenesis. One such mesodermally derived cell type is the mesothelium, which is an epithelial sheet that covers organs in the coelomic cavity and is involved in development of the vascular system. The development of the mesothelium has been well characterized in the heart. The heart mesothelial progenitor cells, the proepicardium (PE), develop independently, migrate onto and over the heart to form the epicardium, and then undergo epithelial-mesenchymal transition (EMT) to give rise to the cells of the coronary blood vessels. Conversely, the progenitors of gut mesothelium are currently unknown, but studies have shown that these cells also undergo EMT and serve as a major source of vascular smooth muscle cells for the gut tube in development. These findings suggest a conserved mechanism of development within both the gut and heart mesothelium. Thus, we hypothesized that the gut mesothelium possesses a similar developmental potential to the epicardium, including: 1) mechanisms by which the progenitor cells develop, and 2) that mesothelial cells have the same potential to incorporate into all mesothelial tissues and contribute cells to any organ when surgically interchanged. First, immunohistochemical studies of avian mesodermal development were conducted to determine the developmental timing and location of mesothelial cells in the gut. To test the above hypotheses direct lineage tracing techniques and a chick-quail chimera system were employed to determine the origin of gut mesothelium. Surprisingly, the gut mesothelium did not develop from an external cell population, but instead from resident cells in the splanchnic mesoderm. However, transplantation of gut mesothelium into the pericardial cavity revealed successful incorporation into epicardium, contribution of smooth muscle cells to vessels, and fibroblasts to the heart. Conversely, PE and epicardial cells transplanted to the peritoneal cavity did not display this same interchangeable capacity. These studies demonstrate that the origins of heart and gut mesothelia differ and only the gut mesothelial cells possess pliable characteristics.

Myeloid-derived suppressor cells (MDSCs) play an important role in cancer progression. Elucidating the mechanisms involved in the expansion and function of these cells is important in the fight against cancer. A microarray comparing splenic Gr-1+CD11b+ cells from tumor-bearing mice and tumor-free mice revealed C/EBPα expression was reduced more than 4-fold in the tumor-derived cells. Based on this finding and published reports, we hypothesized that tumors induce MDSC production through down-regulation of C/EBPα in myeloid cells. In Chapter II, the role of C/EBPα as a negative regulator of MDSC expansion was investigated. Deletion of myeloid C/EBPα in mice yielded an increase in myeloid progenitors and a reduction in mature myeloid cells. Upon inoculation with tumor cells, MDSC production was enhanced nearly two-fold in mice lacking myeloid C/EBPα, while myeloid progenitors were reduced, perhaps because more progenitors became MDSCs in the absence of C/EBPα. In Chapter III, we sought to determine whether C/EBPα is a negative regulator of the immune suppressive and pro-angiogenic properties of MDSCs. When inoculated with tumor cells, MDSC infiltration and tumor vascularization was significantly greater in C/EBPα conditional null mice, resulting in markedly accelerated tumor growth. When MDSCs were injected with tumor cells into mice, C/EBPα ablation resulted in an enhancement in the pro-tumor MDSC phenotype: tumor growth and tumor angiogenesis was significantly greater. We then measured the expression of genes involved in MDSC-mediated immune suppression and angiogenesis and found that C/EBPα deletion resulted in MMP-9, VEGF and iNOS upregulation. Additionally, we observed increased NO production but no difference in arginase expression or immune suppression. Since NO also regulates angiogenesis, we concluded that C/EBPα inhibits the pro-angiogenic but not the immune-suppressive properties of MDSCs. Our findings reveal dual negative roles for C/EBPα in the expansion and pro-angiogenic gene expression in MDSCs, suggesting that overcoming these functions through C/EBPα inhibition may be a critical step in MDSC maturation. Our work indicates that therapy aimed at restoring C/EBP expression in MDSCs may be a viable weapon in the fight against cancer.

<p>Prior research has found that children who pursue revenge goals in minor conflicts with peers are less accepted, have fewer friends, and have friendships of lower quality. Very little research has been devoted to understanding what factors might increase a child's tendency to seek revenge in minor conflicts of interest or in more provocative situations. The present study was designed to assess several variables that may increase revenge motivations in two contexts: minor conflicts of interest and major provocation situations. Of particular interest were the interpretations that children make in conflict, especially interpretations of rejection and disrespect. Two personal dispositions were also investigated, rejection sensitivity and disrespect sensitivity. The latter was assessed using a measure designed for this study. The study also examined whether beliefs about the legitimacy of aggression and beliefs about negative reciprocity moderate the association between negative interpretations and revenge goals. </p><p>Participants were seventh-grade adolescents (n = 367) from a middle school in a midwestern suburban school district. Students were shown vignettes (hypothetical situations) depicting conflict-of-interest situations and major provocation situations. In response to each vignette, participants rated how they would feel, how they would interpret the person's behavior, what their goals would be in the situation, and what behavioral strategies they would enact. Students also completed measures of rejection sensitivity, disrespect sensitivity, reciprocity beliefs, and beliefs about the legitimacy of aggression. Additionally, students indicated which of their grademates were sensitive to rejection and which were sensitive to disrespect.</p><p>Results indicated that adolescents endorsed more rejection and disrespect interpretations, revenge goals, and aggressive strategies in the major provocation situations than in the conflict-of-interest situations. Boys more strongly endorsed revenge goals and aggressive strategies than did girls, although there were not gender differences in rejection or disrespect interpretations. Both rejection and disrespect interpretations were significantly related to revenge goals in both types of situations. In both conflicts of interest and major provocation situations, rejection interpretations mediated the link between rejection sensitivity and revenge goals. In conflicts of interest, disrespect interpretations partially mediated the association between disrespect expectations and revenge goals. In major provocation situations, disrespect interpretations mediated the link between situational disrespect and revenge goals. Although rejection and disrespect interpretations were highly related, when their shared variance was partialed out "disrespect-free" rejection interpretations were associated with revenge goals in both conflicts of interest and in major provocation situations, whereas "rejection-free" disrespect only remained associated with revenge goals in conflict-of-interest situations. Additionally, both legitimacy of aggression beliefs and negative reciprocity beliefs were independently associated with revenge goals in both conflicts of interest and major provocation situations, even after controlling for gender differences and negative interpretations. Further, negative reciprocity beliefs moderated the association between negative interpretations and revenge goals such that adolescents who were high on negative reciprocity beliefs and negative interpretations were much more likely to seek revenge than adolescents who were low on negative reciprocity beliefs and high on negative interpretations. These findings suggest that the continued comparison of disrespect and rejection experiences is warranted and highlight the need to study the personal dispositions and beliefs that may increase revenge goals and vengeful behavior.</p> / Dissertation

Thesis (Ph. D.)--University of Chicago, Department of Philosophy, 2002. / Includes bibliographical references. Also available on the Internet.

Thesis (Ph.D.) -- University of Texas at Arlington, 2009.

Thesis (Ph.D.)--Indiana University, School of Health, Physical Education and Recreation, 2009. / Title from PDF t.p. (viewed on Feb. 4, 2010). Source: Dissertation Abstracts International, Volume: 70-04, Section: A, page: 1425. Adviser: Alan W. Ewert.

Angelman Syndrome (AS) is a devastating neurodevelopmental disorder characterized by developmental delay, speech impairment, movement disorder, sleep disorders and refractory epilepsy. AS is caused by loss of the Ube3a protein encoded for by the imprinted Ube3a gene. Ube3a is expressed nearly exclusively from the maternal chromosome in mature neurons. Mouse models have helped determine the molecular defects in AS, however findings have been inconsistent across laboratories. Work in our laboratory suggested that environmental factors may play a role in the phenotypes observed in AS model mice. As a result, we evaluated the possibility of non-genomic causes of variation in phenotypes observed in AS model mice. Here we demonstrate that maternal status and diet play a large role in the magnitude of a hypomyelination phenotype observed in these mice.

<p>Children are commonly prescribed fluoxetine to manage their depressive symptoms, although evidence suggests many fail to respond to this treatment. Recently, low doses of ketamine were shown to work as a fast-acting and long-lasting antidepressant, however, it is unclear what the long-term effects are of using ketamine in pediatric populations. Thus, this thesis examined whether early-life exposure to ketamine influences the rewarding effects of nicotine in male and female adolescent Sprague- Dawley rats using conditioned place preference. Rats were pretreated with ketamine (0.0 or 20.0 mg/kg) from postnatal day (PD) 21-30 and then assessed for nicotine (0.0, 0.03, 0.1, 0.3, or 0.6 mg/kg) preference during adolescence (PD 32-42). Results indicate that female adolescent rats find nicotine to be more rewarding than male rats, however ketamine pretreatment did not affect nicotine?s effects. These findings suggest that ketamine as an antidepressant in children and adolescents may not produce adverse increases in nicotine reward.