No description available.

Thesis (M.Sc.). / Written for the Division of Experimental Medicine. Title from title page of PDF (viewed 2008/12/04). Includes bibliographical references.

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 2 uppsatser. Även tryckt utgåva.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Phosphorus (P) is one of the three major macronutrients that plants need to grow and survive. When P is scarce, plants utilize a network of characterized responses known as the Phosphate Starvation Response (PSR) to remobilize internal stores of P as well as external P from soil. Emerging evidence shows the PSR is regulated by a specialized group of secondary messenger molecules, inositol pyrophosphates (PP-InsP). PP-InsPs and their precursors, inositol phosphates (InsPs), are important for plant abiotic stress responses, hormone signaling, and other stress responses. While PP-InsPs are critical for plant survival, much about the roles of PP-InsPs and how they are regulated remains to be understood. Further, the enzymes responsible for the synthesis of PP-InsPs in plants have been recently discovered; however, not much is known about the enzymes that degrade PP-InsPs in plants. The goal of the work presented herein is to understand critical aspects of the PP-InsP signaling in plants and leverage this information into a P phytoremediation strategy. To achieve this, I have investigated a group of PP-InsP phosphatases and assessed long-term impacts of depleting PP-InsPs in two plant species, Arabidopsis thaliana (Arabidopsis) and Thlaspi arvense (Pennycress). Exploring the impact of plant PP-InsP phosphatases has allowed me to explore critical aspects of PP-InsP sensing that show great promise for informing P remediation strategies. / Doctor of Philosophy / The Phosphorus (P) crisis presents a major challenge to food security. While Phosphorus (P) is critical for crop growth, P is a nonrenewable and increasingly limited resource. Our global population is fed at the expense of the remaining mineable P reserve, which may be depleted in as early as 30 years. Further, fertilizer runoff from farmland and urban areas poses a dangerous problem as increased nutrients in watersheds toxifies our water supply and aquatic ecosystems. Time is running out to preserve our P supply. New and innovative strategies that reduce fertilizer inputs and watershed pollution are key to securing the global food supply and protecting the environment. Emerging evidence shows plants sense and respond to P using signaling molecules known as inositol pyrophosphates (PP-InsPs). My work and that of others are key in showing that alteration of the levels of PP-InsPs can decrease plant P dependency or cause plants to hyperaccumulate P. Understanding how plants are able to sense, respond, and acquire P is crucial to inform future P phytoremediation strategies to secure global food security.

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 4 uppsatser.

Dissertation (Ph.D.)--University of South Florida, 2008. / Includes vita. Includes bibliographical references. Also available online.

Made available in DSpace on 2014-12-17T15:32:23Z (GMT). No. of bitstreams: 1 AndreiaFC_DISSERT.pdf: 3035785 bytes, checksum: a9769f0a294924c551036d1a098b7d2a (MD5) Previous issue date: 2014-02-12 / A displasia epitelial (DE) oral ? uma desordem potencialmente maligna (DPM), cujo diagn?stico e grada??o histol?gica se baseiam nas suas altera??es arquiteturais e citol?gicas. Para avaliar o risco de transforma??o maligna dessas les?es de forma mais precisa ? fundamental entender e localizar altera??es gen?ticas e epigen?ticas nas c?lulas displ?sicas, as quais podem ajudar a compreender melhor a progress?o para a malignidade. Dessa forma, o presente estudo objetivou avaliar a imunoexpress?o de EGFR e PTEN nas DEs orais e relacionar esse aspecto com as caracter?sticas cl?nicas e grada??o histol?gica pelo sistema bin?rio (baixo e alto risco de transforma??o maligna). Para tanto, foram selecionados 20 casos de DE de alto risco e 20 de baixo risco para serem submetidos ? an?lise imunoistoqu?mica para os biomarcadores supracitados. A imunomarca??o de cada caso foi avaliada semiquantitativamente atrav?s de escores e quanto ? localiza??o nos estratos epiteliais. A an?lise estat?stica foi realizada atrav?s dos testes de Mann-Whitney, Qui-quadrado de Pearson, Exato de Fisher e de correla??o de Spearman com n?vel de signific?ncia estabelecido em 5%. Os resultados mostraram que 57,5% dos pacientes eram do g?nero feminino, a m?dia de idade foi de 57,5 anos, 42,5% foram diagnosticados clinicamente como leucoplasia e a maioria dos casos foi proveniente de les?es localizadas na l?ngua (32,5%). De forma geral, g?nero e idade n?o exerceram influ?ncia na imunoexpress?o do EGFR e PTEN. A express?o do EGFR foi observada em 100% dos casos, nos quais houve predom?nio do escore 3 (75%) e imunoreatividade em todas as camadas epiteliais (55%), independente da grada??o histol?gica (p = 0,453 e p = 0,204, respectivamente). O PTEN revelou positividade de marca??o em 87,5% dos casos, nos quais observou-se predom?nio do escore 0 (55%) e imunoreatividade limitada ? camada basal (40%), por?m sem diferen?as significativas entre os grupos histol?gicos (p = 0,904 e p = 0,915, respectivamente). Por fim, quando analisados, em conjunto, os 40 casos de DEs, foi observada uma fraca correla??o positiva, estatisticamente significativa, entre os padr?es de imunoexpress?o do EGFR e do PTEN (r = 0,317; p = 0,046). Com base nesses resultados, altera??es no padr?o de express?o do EGFR e PTEN sugerem que essas prote?nas participam de processos moleculares relacionados com a carcinog?nese em mucosa oral

Cancer is the second leading cause of death among men and women after heart disease. Though our knowledge associated with the complexities of the cancer network has significantly improved over the past several decades, we have only recently started to get a more complete molecular understanding of the disease. To better comprehend signaling pathways that prevent disease development, we focused our efforts on investigating endogenous tumor suppression networks in controlling effectors of cancer cell survival and proliferation. Survivin is one such effector molecule that controls both cell proliferation and survival. In order to identify how this protein is overexpressed in cancer cells as opposed to normal cells, we looked at signaling molecules that negatively regulate this inhibitor of apoptosis protein. PTEN and caspase 2 are two of the identified proteins that utilize their enzymatic activity to suppress tumor growth by inhibiting downstream cell survival effectors, namely survivin. PTEN uses its phosphatase activity to suppress the PI3K/AKT pathway and maintain cellular homeostasis. In the absence of AKT activity, FOXO transcription factors are able to target downstream gene expression and regulate cell proliferation and survival. Here we have identified survivin as a novel gene target of FOXO, which binds to a specific promoter region of survivin and suppresses its transcription. Alternatively, caspase 2 uses its catalytic activity to suppress survivin gene expression by targeting the NFκB pathway. Caspase 2 acts by cleaving a novel substrate known as RIP1 that prevents NFκB from entering the nucleus, thus inhibiting target gene transcription. Interestingly, survivin is known to be a direct gene target of NFκB that controls cancer cell survival. In our investigation, we found that survivin is downregulated upon caspase 2 activation via the NFκB pathway, resulting in decreased cell cycle kinetics, increased apoptotic threshold and suppressed tumor growth in mice. These studies conclude that survivin is a common effector molecule that is regulated by tumor suppressors to maintain cellular homeostasis. However, upon deactivation of the tumor suppressor pathway, survivin is deregulated and contributes significantly to disease progression. These observations may lead to potential therapeutic implications and novel targeting strategies that will help eradicate harmful cancer cells and spare surrounding healthy cells; often the most persistent problem of most conventional chemotherapy.

In der Entwicklung des peripheren Nervensystems formen Schwannzellen eine Myelinscheide um Axone mit einem Durchmesser von mehr als 1 μm durch die Bildung multipler kompakter Membranschichten. Voraussetzung einer optimalen Nervenleitgeschwindigkeit ist dabei ein physiologisches Verhältnis der Dicke der Myelinscheide zu dem jeweiligen Axondurchmesser. Eine zentrale Rolle spielt dabei der axonale EGF-like growth factor NRG1 Typ III, der ErbB2/3- Rezeptoren der Schwannzelle bindet. Der PI3K-AKT-Signalweg ist ein bekannter intrazellulärer Effektor des ErbB2/3-Rezeptors und wurde bereits mit dem Prozess der Myelinisierung in Verbindung gebracht. Um die spezifische Funktion des PI3K-AKT-Signalwegs in Schwannzellen zu erforschen, generierten wir mit Hilfe des Cre/LoxP-Systems Mausmutanten, die eine zellspezifische Inaktivierung des Gens Phosphatase and Tensin Homolog (Pten) in myelinisierenden Gliazellen aufweisen (Pten-Mutanten). Der Verlust der Lipidphosphatase PTEN führte zu einer Anreicherung ihres Substrates, des second messenger Phosphatidyl-(3,4,5)-Trisphosphat (PIP3), und damit zu einer gesteigerten Aktivität des PI3K-AKT-Signalwegs in den Schwannzellen der Pten-Mutanten. Wir beobachteten in den Pten-Mutanten eine ektopische Myelinisierung von unmyelinisierten C- Faser-Axonen sowie eine Hypermyelinisierung von Axonen bis 2 μm Durchmesser. Bei Axonen über 2 μm Durchmesser kam es zu Myelinausfaltungen und fokalen Hypermyelinisierungen (Tomacula) anliegend an Regionen des unkompakten Myelins (Paranodien und Schmidt- Lantermann-Inzisuren). Weiterhin bildeten die mutanten Remak-Schwannzellen unkompakte Membranwicklungen um nicht-myelinisierte C-Faser-Axone und um Kollagenfaserbündel aus („Remak-Myelin“). Sowohl in den Regionen unkompakten Myelins als auch in Remak- Schwannzellen konnte eine erhöhte Aktivität des PI3K-AKT-Signalwegs nachgewiesen werden. Vermutlich setzt die Anreicherung von PIP3 mit Überaktivierung des PI3K-AKT-Signalwegs in den mutanten Gliazellen einen zellautonomen Prozess der Umwicklung von Axonen in Gang. Die zusätzliche Bildung von „Remak-Myelin“ um Kollagenfasern, die keine Membranoberfläche besitzen, weist darauf hin, dass dieser Prozess nicht von einer bidirektionalen axo-glialen Kommunikation abzuhängen scheint. Die beobachteten Tomacula und Myelinausfaltungen zeigten Ähnlichkeiten mit Mausmodellen für hereditäre Neuropathien des Menschen, wie HNPP und CMT4B. Wir vermuten, dass PTEN im unkompakten Myelin unkontrolliertes Membranwachstum verhindert und dass eine gestörte Balance von Phosphoinositiden einen Pathomechanismus von tomaculösen Neuropathien darstellt. Somit identifizieren wir den PI3K-AKT-Signalweg als ein mögliches Ziel zukünftiger Therapiekonzepte für hereditäre Neuropathien des Menschen.