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1
Maxe, Liza, Kiana Entezarjo, and Douglas Karegren. "Swap Notch." Thesis, Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:hh:diva-40654.
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Quillard, Thibaut. "Importance de la voie Notch dans la dysfonction endothéliale en transplantation : régulation et fonctions des récepteurs Notch2 et Notch4." Nantes, 2008. https://archive.bu.univ-nantes.fr/pollux/show/show?id=6bdde4e3-76bb-4a01-9661-3ee28931b379.
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Notch joue un rôle important dans la survie, la prolifération et la transdifférenciation des cellules endothéliales (CE). Ces mécanismes sont tout particulièrement importants dans l'artériosclérose du greffon (AG). L'objectif de ce travail est de définir la régulation et le rôle de Notch dans la dysfonction des CE associée à l'AG. Nous avons tout d'abord étudié la régulation des molécules Notch (récepteurs, ligands et effecteurs) au cours de l'activation des CE. Ainsi, le TNFα oriente le profil Notch vers une forte diminution de Notch4 et une augmentation de Notch2, respectivement par les voies NF��B et PI3K. Cet effet est toutefois associé à une baisse globale de l’activité CBF1. La baisse du récepteur endothélial Notch4 est, de plus, associée à l’AG dans un modèle d’allogreffe cardiaque chez le rat où le TNFα, TGFβ et IL10 sont fortement exprimés. Le blocage de Notch4 et de hes1 par ARN interférence favorise l’expression de VCAM-1, induit l’apoptose et altère la cicatrisation endothéliale. L’expression constitutive de Notch2ICD grâce à un adénovirus recombinant induit l’apoptose des CE par une forte répression de gènes anti- (survivine, April) et pro-apoptotiques (Bim, DAPK2, HRK, DR5, CD40). La fonction pro-apoptotique de N2ICD dépend essentiellement de l’inhibition de la survivine. L'extinction de Notch2 augmente l'expression de la survivine et protège les CE de l’apoptose. L'ensemble de ces travaux montre une interaction entre les voies du TNF et Notch au cours de la dysfonction endothéliale, propose un rôle pour Notch4 dans la prévention de la dysfonction endothéliale dans l'AG et démontre l'importance de Notch2 dans la survie des CE par la régulation de la survivineNotch plays major roles in endothelial cells (EC) survival, proliferation and transdifferentiation. These events are particularly implicated in transplant arteriosclerosis (TA). This work aims to define Notch molecules regulation and its functional relevance in graft EC. We first studied Notch family members (receptors, ligands and effectors) regulation during EC activation by cytokines. We show that TNFα induced a switch in Notch expression pattern by a strong down-regulation of Notch4 and an increase in Notch2, respectively dependent on NFkB and PI3K pathways. This effect is associated with a global decrease in CBF1 activity and an opposite regulation of hes1 and hey1. Decrease in EC-restricted Notch4 expression is also associated with TA in a rat cardiac allograft model where TNFα, TGFβ and IL10 are strongly expressed. Inhibition of Notch4 and hes1 by siRNA enhances VCAM1 expression, induces apoptosis and impairs endothelial injury repair, suggesting that Notch4 expression is required to maintain EC survival and quiescence. To study the role of Notch2 in EC, we constructed a recombinant adenovirus for Notch2ICD (N2ICD). Constitutive expression of N2ICD leads to EC apoptosis associated with a drastic repression of pro- (survivin, april) and anti-apoptotic genes (bim, DAPK2, HRK, DR5, CD40). Effect of N2ICD is mainly dependent on survivin inhibition. Accordingly, Notch2 knock-down increases survivin expression and protects EC from anoïkis. Altogether, our results reveal crosstalks between TNF and Notch signaling during endothelial dysfunction, propose a role for Notch4 in preventing TA-related EC dysfunction and for Notch2 role in EC survival through survivin regulation
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Huang, Yuchen. "Adaptive Notch Filter." PDXScholar, 1994. https://pdxscholar.library.pdx.edu/open_access_etds/4802.
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The thesis presents a new adaptive notch filter (ANF) algorithm that is more accurate and efficient and has a faster convergent rate than previous ANF algorithms. In 1985, Nehorai designed an infinite impulse response (UR) ANF algorithm that has many advantages over previous ANF algorithms. It requires a minimal number of parameters with constrained poles and zeros. It has higher stability and sharper notches than any ANF algorithm until now. Because of the special filter structure and the recursive prediction error (RPE) method, however, the algorithm is very sensitive to the initial estimate of the filter coefficient and its covariance. Furthermore, convergence to the true filter coefficient is not guaranteed since the error-performance surface of the filter has its global minimum lying on a fairly flat region. We propose a new ANF algorithm that overcomes the convergence problem. By choosing a smaller notch bandwidth control parameter that makes the error-performance surface less flat, we can more easily detect a global minimum. We also propose a new convergence criterion to be used with the algorithm and a self-adjustment feature to reset the initial estimate of the filter coefficient and its covariance. This results in guaranteed convergence with more accurate results and more efficient computations than previous ANF algorithms.
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O'Neill, Christine F. "Notch Regulation of Human Breat Cancer Progression: Contrasting Roles for Notch Signaling." Fogler Library, University of Maine, 2007. http://www.library.umaine.edu/theses/pdf/O'NeillCF2007.pdf.
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Poudel, Rajeeb. "Single Notch Versus Multi Notch Credit Rating Changes and the Business Cycle." Thesis, University of North Texas, 2015. https://digital.library.unt.edu/ark:/67531/metadc848118/.
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Issuers’ credit ratings change by one or more notches when credit rating agencies provide new ratings. Unique to the literature, I study the influences affecting multi notch versus single notch rating upgrades and downgrades. For Standard & Poors data, I show that rating changes with multiple notches provide more information to the market than single notch rating changes. Consistent with prior literature on the business cycle, I show that investors value good news rating changes (upgrades) more in bad times (recession) and that investors value bad news rating changes (downgrades) more in good times (expansion).
I model and test probit models using variables capturing the characteristics of the previous issuer’s credit rating, liquidity, solvency, profitability, and growth opportunity to determine the classification of single notch versus multi notch rating changes. The determinants of multi notch versus single notch rating changes for upgrades and downgrades differ. Business cycle influences are evident.
Firms that have multi notch rating upgrades and downgrades have significantly different probit variables vis-à-vis firms that have single notch rating upgrades and downgrades. The important characteristics for determining multiple notch upgrades are a firm’s prior rating change, prior rating, cash flow, total assets and market value. The important characteristics for determining multiple notch downgrades are a firm’s prior rating change, prior rating, current ratio, interest coverage, total debt, operating margin, market to book ratio, capital expenditure, total assets, market value, and market beta. The variables that differ for multi notch upgrades in recessions are cash flow, net income, operating margin, market to book ratio, total assets, and retained earnings. The variables that differ for multi notch downgrades in expansions are a firm’s prior rating change, current ratio, interest coverage ratio, debt ratio, total debt, capital expenditure and market beta.
The power of the explanatory tests improves when the stage of the business cycle is considered. Results are robust to consideration of rating changes across rating categories, changes from probit to logit, alternative specifications of accounting variables, lags and leads of recessions and expansions timing, Fama and French industry adjustments, and winsorization levels of variables.
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Serafin, Valentina. "Notch3 signalling promotes tumour growth in colorectal cancer: implication for Notch target therapy." Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3422188.
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It is well known that aberrant activation of the Notch pathway plays a critical role in the pathogenesis of T cell acute lymphoblastic leukaemia (T-ALL) and of certain solid tumors including lung, breast and ovarian cancer. In particular, increased Notch1 activity has been observed in intestinal adenoma, partially accomplished by β-catenin-mediated up-regulation of the Notch ligand Jagged-1.
Whether further mechanisms of Notch activation exist and other Notch receptors might be involved in colorectal cancer (CRC) has not been investigated so far. In this study we investigated the possible involvement of Notch3 signaling in CRC, and the possible therapeutic implications.
Intrigued by the observation that Notch3 mRNA and protein are over-expressed in a subset (20%) of human CRC, we sought to investigate how Notch3 modulates oncogenic features of CRC cells. By exploiting xenografts of CRC cells with different tumorigenic properties in mice, we found that the aggressive phenotype was associated with altered expression of components of the Notch pathway, including augmented expression of Delta-like 4 (DLL4) and Jagged-1 ligands and increased levels of the Notch3 transcript and intracellular domain (ICD). Stimulation with immobilized recombinant DLL4 dramatically increased Notch3 expression and Notch signaling. Moreover, forced expression of an active form of Notch3 mirrored effects of DLL4 stimulation and increased tumor formation. Conversely, blocking Notch3 signaling resulted in perturbation of the cell cycle followed by reduction of cell proliferation and inhibition of tumor growth.
Moreover, we observed that these CRC cells have also different metastatic potential in terms of number and dimension when injected intravenously in mice.
Lung metastases formed by CRC cells expressed Notch3, but the number or size was not significantly reduced by anti-Notch2/3 treatment.
Overall, these findings indicate that Notch3 receptor can modulate the tumorigenic
properties of CRC cells, and that DLL4 contributes to sustain Notch activity in DLL4-expressing tumors. Further studies are necessary to clarify the role of Notch3 in metastasis and design effective target therapies.E’ ormai noto da alcuni anni che un’aberrante attivazione della via di segnalazione di Notch gioca un ruolo critico nella patogenesi della leucemia linfoblastica acuta a cellule T (T-ALL) e di alcune neoplasie solide come il cancro del polmone, della mammella e dell’ovaio. Inoltre, una marcata attivazione del recettore Notch1 è stata osservata negli adenomi intestinali ed è correlata all’aumentata espressione del ligando Jagged-1 indotta dall’attivazione del pathway Wnt-APC-β-catenina. E’ stato inoltre dimostrato che questa pathway, insieme a quella di Notch, interviene nella regolazione della proliferazione e del differenziamento delle cellule epiteliali della mucosa intestinale normale. Attualmente, non si sa ancora se altri meccanismi di attivazione della pathway di Notch, oltre a quello ligando-dipendente, siano operativi nel CRC e nemmeno se possano essere coinvolti altri recettori della stessa famiglia. In questo studio, abbiamo cercato di chiarire il possibile coinvolgimento di Notch3 nel CRC. Basandoci sull’osservazione che Notch3 risulta essere frequentemente overespresso sia a livello di mRNA che di proteina nei campioni umani di CRC, abbiamo cercato di chiarire come il recettore Notch3 potesse modulare le proprietà tumorigeniche delle cellule di CRC. A tale scopo, si sono rivelati particolarmente utili alcuni xenotrapianti di cellule umane di CRC che presentano una diversa aggressività in topi NOD/SCID. Infatti, utilizzando i tumori sperimentali, abbiamo potuto dimostrare che l’espressione dei diversi componenti del pathway di Notch risulta essere significativamente elevata nella variante aggressiva rispetto a quella dormiente. In particolare si è osservata un’ aumentata espressione dei ligandi DLL4 e Jagged-1 ed un incremento dei livelli del trascritto di Notch3 e della forma attiva del recettore nei tumori che crescono più rapidamente. Una simile up-regolazione di Notch3 con un’aumentata attivazione della via di segnalazione si è osservata in seguito a stimolazione delle cellule di CRC in vitro con il ligando DLL4 ricombinante. Analogamente, anche l’overespressione di una forma attiva del recettore Notch3 in queste stesse cellule conferisce loro una maggiore capacità proliferativa e favorisce la formazione di tumori in vivo. Al contrario, si è visto che l’inattivazione del pathway mediante silenziamento genico di Notch3 nelle cellule aggressive di CRC, determina significative alterazioni del ciclo cellulare con conseguente riduzione nella proliferazione in vitro e un ritardo nella crescita dei tumori in vivo. Complessivamente, questi risultati dimostrano che il recettore Notch3 può modulare le proprietà tumorigeniche delle cellule di CRC, in particolare contribuendo a mantenere elevata l’attivazione della via di Notch nei tumori esprimenti nel loro microambiente tumorale alti livelli di DLL4. Inoltre, l’inoculo della variante più aggressiva rispetto a quella dormiente per via endovenosa in topi NOD/SCID ha mostrato che le cellule di CRC non hanno solo una diversa capacità tumorigenica, ma anche una differente capacità metastatica a livello polmonare, sia in termine di numero che di dimensioni delle metastasi osservate. Basandoci sui risultati fin qui ottenuti, e su uno studio recentemente pubblicato in cui è stato dimostrato come il pathway di Notch sembra essere coinvolto anche nel processo di metastatizzazione, abbiamo condotto un primo esperimento pilota che prevedeva, in topi portatori di metastasi polmonari, il blocco dei recettori Notch3 e Notch2 mediante l’impiego di un anticorpo neutralizzante. Sfortunatamente i risultati ottenuti non hanno fino ad ora mostrato una riduzione significativa nel numero e nelle dimensioni delle metastasi analizzate: l’analisi dei livelli di alterazione di Notch dopo il trattamento è in corso. A conclusione dello studio le nostre osservazioni rappresentano un punto di partenza per un futuro sviluppo di terapie che abbiano Notch3 come bersaglio per il trattamento di un sottogruppo di casi di CRC.
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Rangarao, Kaluri Venkata. "Adaptive digital notch filtering." Thesis, Monterey, California. Naval Postgraduate School, 1991. http://hdl.handle.net/10945/26345.
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Singh, Nita. "The expression of the Notch receptors, Notch ligands, and the Fringe genes in hematopoiesis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq29262.pdf.
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Ferreira, António Carlos Ribeiro. "Notch signaling pathway in gastric carcinogenesis: E-cadherin inactivation on Noth-dependent cell survival." Doctoral thesis, Faculdade de Medicina da Universidade do Porto, 2010. http://hdl.handle.net/10216/55364.
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Ferreira, António Carlos Ribeiro. "Notch signaling pathway in gastric carcinogenesis: E-cadherin inactivation on Noth-dependent cell survival." Tese, Faculdade de Medicina da Universidade do Porto, 2010. http://hdl.handle.net/10216/55364.
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Prexl, Andrea. "Der Notch-Signaltransduktionsweg in Hydra." Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-119290.
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Ortica, Sara. "Notch pathway in liver progenitors." Paris 7, 2012. http://www.theses.fr/2012PA077175.
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La voie de signalisation Notch intervient dans la communication intercellulaire. Chez les mammifères, quatre récepteurs Notch (Notch 1-4) sont exprimés. Ils sont présents sous forme hétérodimérique à la surface cellulaire. Après l'interaction avec un ligand, Notch est activé par une cascade de clivages. La forme activée du récepteur (Nie, pour "Notch intracellulaire") est alors transportée dans le noyau, où elle active la transcription des gènes cibles. Pour mieux comprendre l'influence de Notch sur les progéniteurs hépatiques nous avons utilisé un système in vitro basé sur des cellules bipotentielles issues d'un foie murin embryonnaire (BMEL : Bipotential Mouse Embryonic Liver cells). Ces cellules peuvent être cultivées à l'état indifférencié, ou orientées vers un lignage hépatocytaire ou cholangiocytaire. Notch est actif à l'état indifférencié, et nous avons démontré que son inhibition induit une diminution dose-dépendante de la prolifération des BMEL, en réduisant l'entrée dans la phase S du cycle. Nic2 et Nic4 peuvent complémenter cet effet sur la prolifération, alors que Nic3 réduit la prolifération et augmente la polyploïdie. En outre, Nic3 permet la différenciation hépatocytaire, alors que les autres récepteurs doivent être inhibés pour permettre ce processus. En conclusion, nous avons montré que les quatre récepteurs Notch ont des rôles non redondants au cours du développement hépatique. Nous avons également testé les effets de Num. B, un inhibiteur de Notch, exprimé dans les hépatocytes. L'expression de Numb réduit la prolifération des BMEL, augmente leur volume et leur polyploïdie, avec une expression de marqueurs hépatocytaireNotch signalling is a highly conserved pathway that mediates short-range communications inter-cells. In mammals, four Notch receptors (Notch 1-4) are present. The receptor stands as a transmembrane heterodimer at the cell surface and it is activated after the interaction with a ligand. After a series of cleavages the activated form of the receptor (Nie) is translocated into the nucleus, where it activates target gene transcription. To get a better insight into the mechanisms of Notch function in liver progenitors we chose to use an in vitro System based on Bipotential Mouse Embryonic Liver (BMEL) cells. These progenitors can be maintained in the undifferentiated state or differentiated into hepatocytes or cholangiocytes. Our results show that Notch is active in undifferentiated BMEL cells, and that its inhibition decreases BMEL cell proliferation in a dose-dependent manner, through inhibition of S phase entry. Nic2 and Nic4 can complement the inhibition on proliferation, while Nic3 impairs proliferation and increases multinucleation. Moreover, we find that Nic3 is conducive of hepatocytic specification, while the other Notch receptors inhibit this fate. In conclusion, we show that the four Notch receptors have non-redundant roles during liver development, and that the type of the receptor involved can be more important than the overall pathway activation. Finally, we tested the effects of Numb, a Notch inhibitor upregulated upon hepatocytic commitment. Expression of Numb in undifferentiated progenitors reduces their proliferation rate, and induces a hepatocyte-like phenotype with large and multinucleated cells expressing hepatocytic markers
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Jangsri, Venus. "Infinite impulse response notch filter." Thesis, Monterey, California. Naval Postgraduate School, 1988. http://hdl.handle.net/10945/23269.
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Approved for public release; distribution is unlimitedA pipeline technique by Loomis and Sinha has been applied to the design of recursive digital filters. Recursive digital filters operating at hitherto impossibly high rates can be designed by this technique. An alternate technique by R. Gnanasekaran allows high speed implementation using the state-space structure directly. High throughput is also achieved by use of pipelined multiply-add modules. The actual hardware complexity will depend upon the number of pipeline stages. These techniques are used for the design of the I IR notch filter and finally, a comparison of the performance and complexity of these two techniques is presented.
http://archive.org/details/infiniteimpulser00jang
Lieutenant, Royal Thai Navy
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Thomas, James W. "Efficient narrow-band notch filter." Master's thesis, This resource online, 1994. http://scholar.lib.vt.edu/theses/available/etd-02022010-020151/.
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Jaekel, Robert. "Regulation des Notch-Signalweges durch Lethal (2) giant discs (Lgd) und durch die Notch-Liganden." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=983735255.
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Schüller, Martina. "Biochemische Charakterisierung der humanen Notch 1 und Notch 3 Rezeptoren und Analyse der Expression des humanen Notch 1 Rezeptors auf Zell-Linien und histologischen Präparaten." Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-60321.
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Benson, Robert A. "Notch and CD4+ T cell function." Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/25108.
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Activation of purified murine CD4+ T cells enhanced expression of the Notch target gene hes1 and induced differential expression of Notch receptors and ligands compared to unstimulated cells. Surface staining for Notch 1 revealed that unstimulated cells expressed this receptor at the membrane. Activation of T cells induced capping of Notch1, which was found to co-localise with CD4. Capping of surface Notch and co-localisation with CD4 upon T cell activation was reminiscent of immunological synapse formation, suggesting that Notch may interact directly with T cell receptor signalling. Notch signalling was attenuated in CD4+ T cells using a γ-secretase inhibitor, allowing assessment of Notch function in determining effector function. Notch signal inhibition in the context of anti-CD3-Ab stimulation, resulted in inhibition of TNFα, IFNγ, IL-4 and IL-10 secretion. Blockade of Notch signalling where cells were stimulated with anti-CD3/28-Ab did not down-regulate TNFα, IFNγ or IL-4 secretion, but IL-10 was inhibited. Notch signalling may thus be important as a co-stimulator when CD28 signalling is limiting. Naturally occurring CD25+ CD4+ T regulatory cells and in vitro generated TrI cells were examined for expression of Notch pathway components to ascertain if Notch may be involved in mediating regulatory function. Both populations were found to express higher levels of the Notch ligand Delta 1 than non-regulatory CD4+ T cells. Inhibition of Notch signalling did not affect the ability of CD25+ CD4+ T cells to regulate proliferation of CD4+ CD25+ T cells, but did reduce secretion of IL-10. These findings indicate that Notch receptors and ligands are expressed by CD4+ T cells. Notch may also be a component of the immune synapse and potentially modulates CD4+ T cell effector function through regulation of cytokine secretion, particularly IL-10.
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Petersson, Johan. "Notch signaling pathways inthe obese mouse." Thesis, Örebro universitet, Institutionen för medicinska vetenskaper, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-66818.
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Karlström, Helena. "Notch receptor processing and CNS disease /." Stockholm : [Karolinska institutets bibl.], 2002. http://diss.kib.ki.se/2002/91-7349-300-7/.
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Glittenberg, Marcus Thorleiv. "Serrate mediated regulation of Notch signalling." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614149.
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Beggs, Barry John. "Notch signalling and B-cell activation." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619856.
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Housden, B. "Notch targets and EGFR pathway regulation." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604264.
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Previous work in the lab identified potential Notch targets in a muscle related Drosophila cell line using a combination of genome wide expression array, chromatin immunoprecipitation (ChIP) and bioinformatics approaches. My project was focussed on investigating the regulation of EGFR pathway components by Notch signalling and unravelling mechanisms by which this crosstalk is dependent on context. Previous genetic studies have demonstrated extensive crosstalk between the Notch and EGFR pathways. The unexpected result from the genome wide studies was the overrepresentative of EGFR pathway components that were direct targets. This group of nine targets included both positive and negative regulators of the pathway. One of my first goals was to validate these as direct targets, for which I used a combination of luciferase and in-vivo reporter assays. To address the question of how activation and inhibition of the EGFR pathway is resolved into a final effect on EGFR output the temporal profiles of the different components was investigated. Initial results show that there are distinct temporal activation profiles for different EGFR related genes following Notch activation. This is predicted to lead to an initial inhibition of EGFR signalling (due to fast initial inhibitor accumulation) followed by an activation of signalling (due to inhibitor decrease and activator production). Current work on this project is focussed on identifying different classes of temporal response at the genome wide scale and asking whether there is any consistency in the types of genes that adopt specific profiles. One of the challenges in dissecting the response to Notch is understanding why genes respond only in certain contexts. Argos, which encodes an EGFR inhibitor, is one example of a gene whose response to Notch signalling is context dependent. My results show that argos is positively regulated in the muscle progenitors. However, in the wing pouch, argos expression is reduced upon Notch activation. I have mapped these contrasting responses to separable enhancers, one active in the muscle precursors that I have shown to be directly regulated by Notch and the other active in the wing pouch where it integrates both EGFR and Notch signals. The latter is mediated by the Notch target E(spl)mβ and is therefore indirectly affected by Notch. Further studies to distinguish the components acting through the different enhancers revealed that the bHLH protein Twist is required for Notch activation of the muscle precursor enhancer and the wing pouch enhancer activity appears to involve an interplay between general activation and restricted repressors.
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Nichols, II James Tucker. "DSL-ligand endocytosis and notch signaling." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1692099791&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Deftos, Michael Laing. "Notch signaling in T cell development /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/8364.
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Ubezio, B. "Notch signalling dynamics during sprouting angiogenesis." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1420272/.
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During sprouting angiogenesis endothelial tip and stalk cells specification is regulated by a lateral-inhibition system involving Dll4/Notch and Vegf signalling pathways, the Vegf-Dll4/Notch negative feedback loop. Experimental observations and computational modelling have recently illustrated how this process is predicted to be extremely dynamic and exquisitely sensitive to Vegfa. In this study, we combined several in vitro and in vivo approaches in order to dissect the dynamic regulation of Dll4/Notch signalling driven by Vegfa, and to analyse the effects that this regulation has on vessel morphology. By measuring total Dll4 mRNA and protein levels in cultured endothelial cells, we initially demonstrated that Dll4/Notch dynamic activity is regulated by Vegfa in a dose-dependent manner in vitro. We then generated two novel fluorescence Dll4 reporters and by monitoring the relative signals within ES-derived sprouting embryoid bodies, we showed that Dll4 expression fluctuates in individual endothelial cells in correlation with dynamic cell movement. Importantly, we also found that Notch signalling activity, through the Vegf-Dll4/Notch feedback system, undergoes a phase transition between two distinct operational modes, depending on Vegfa concentration: physiological Vegfa levels lead to highly differential, ‘single cell’ Dll4 dynamics, associated with sustained sprout elongation and branching, while pathologically high Vegfa levels result in Dll4 synchronised fluctuations between clusters of cells, leading to sprouting and branching disruption and vessel enlargement. Finally, since we could observe synchronised cell clusters of Dll4 expression by Dll4 reporter and protein staining in the vessel expansions of Vegfa-injected and retinopathy model retinas, we suggested that synchronization is an important principle of vessel malformation in disease. We anticipate therefore that a better understanding of Notch signalling dynamics and its dependence on Vegfa concentrations will have important therapeutic implications.
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Giovannini, Catia <1975>. "Ruolo dei geni Notch nell'epatocarcinoma umano." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2007. http://amsdottorato.unibo.it/196/1/TESI.pdf.
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Giovannini, Catia <1975>. "Ruolo dei geni Notch nell'epatocarcinoma umano." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2007. http://amsdottorato.unibo.it/196/.
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MOREL, VERONIQUE. "Mecanismes moleculaires de la voie de signalisation notch. Etude de la regulation de single-minded par notch." Paris 6, 2001. http://www.theses.fr/2001PA066173.
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Notch est le recepteur transmembranaire d'une voie de signalisation intercellulaire conservee du nematode a l'homme. Le modele classique de la voie notch propose que l'activation de notch par son ligand delta induit une cascade proteolytique aboutissant a la coupure du domaine intracellulaire de notch. Celui-ci migre dans le noyau ou il s'associe au facteur de transcription suppressor of hairless (su(h)) et active l'expression des genes cibles. Au cours de ma these, j'ai etudie le controle de l'expression de single-minded (sim) par la voie de signalisation notch dans l'embryon de drosophile. J'ai montre que sim est une nouvelle cible de la voie notch. L'etude de la contribution de su(h) a l'expression de sim m'a permi d'etablir que su(h) reprime l'expression de sim et que l'activation de la voie notch conduit a un echange au niveau de su(h) entre une activite repressive et une activite activatrice. Hairless est un antagoniste de la voie notch. Il avait ete propose que hairless inhibe l'activite notch en titrant su(h) de l'adn, l'empechant ainsi de medier l'activation par notch. Or hairless est requis pour la repression de l'expression de sim. De plus, su(h) et hairless cooperent pour antagoniser la voie notch et pour reprimer l'expression de sim. En outre, hairless et su(h) forment un complexe a l'adn. Enfin, hairless interagit avec le corepresseur dctbp in vitro. La repression associee a su(h) impliquerait donc la formation a l'adn d'un complexe su(h)/hairless capable de recruter dctbp. Enfin, j'ai montre que la voie notch est activee au contact du domaine d'expression de snail et que snail est requis pour modifier la localisation subcellulaire de delta. Il semblerait que snail controle l'activation de la voie notch en modifiant la localisation de delta. L'implication de snail dans le controle de l'expression de sim permet d'expliquer son profil d'expression discret le long de l'axe dorso-ventral.
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Pigatti, Fernanda Mombrini. "Participação da via Notch em lesões labiais fotoinduzidas." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/23/23141/tde-08082016-104155/.
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A intensa exposição ao Sol sujeita o lábio, principalmente o inferior, aos danos provocados pela absorção de radiação ultravioleta (UV). O carcinoma epidermoide é a neoplasia maligna que se desenvolve nos lábios após exposição crônica prolongada aos raios UV e acredita-se que todos os casos sejam precedidos pela desordem potencialmente maligna denominada queilite actínica. Ambas as lesões são causados pelos efeitos nocivos da radiação UV agindo diretamente sobre o DNA, por meio do fenômeno da fotocarcinogênese. Nesse processo, a radiação provoca mutações que são capazes de causar a iniciação, progressão e a promoção de neoplasias. No entanto, é também importante considerar que outros eventos moleculares, além das mutações, estão envolvidos na iniciação e progressão do câncer. Alterações moleculares com ganho ou perda de função de componentes da via de sinalização Notch estão envolvidas em diferentes tipos de cânceres hematológicos e sólidos. Entretanto, a participação da sinalização Notch em câncer de lábio ainda é desconhecida. Assim, o objetivo desse trabalho foi investigar se a via Notch está relacionada às lesões de queilite actínica e de carcinoma epidermoide de lábio e sua participação na fotocarcinogênese bucal. Para isso, foram utilizados 45 casos de queilite actínica, 15 casos de carcinoma epidermoide de lábio e 05 casos de lábio com aspecto de normalidade, nos quais foi analisada a expressão de Notch1 e Jagged1 por meio da técnica de imuno-histoquímica. Os resultados demonstraram que houve perda da expressão de Notch1 em 40% dos carcinomas epidermoides de lábio, sugerindo que a expressão reduzida de Notch1 pode converter os queratinócitos a um estado ativado e imaturo. Observou-se ainda, diferença nos padrões de marcação de Nocth1 e Jagged1 nas células epiteliais sugerindo que o sinal da via Notch seja transmitido a partir de uma célula apical para uma célula basal devido a localização das células que expressam o receptor e das que expressam o ligante. Concluiu-se, assim, que os resultados imuno-histoquímicos não apontam a uma regulação diferencial da expressão da proteína Notch1 e Jagged1 em lesões UV induzidas.The intense exposure to the sun subject the lips, particularly the lower, the damage caused by the absorption of ultraviolet (UV) radiation. The squamous cell carcinoma is a malignant tumor that develops on the lips after prolonged chronic exposure to UV rays and it is believed that all cases are preceded by potentially malignant disorder called actinic cheilitis. Both lesions are caused by the harmful effects of UV radiation acting directly on the DNA, through the phenomenon of photocarcinogenesis. In this process, the radiation causes mutations that are capable of causing the initiation, progression and promotion of cancer. However, it is also important to consider that other molecular events, apart from the mutations are involved in the initiation and progression of cancer. Molecular abnormalities with gain or loss of Notch pathway components function are involved in several types of hematological and solid cancer. However, the participation of Notch signaling in lip cancer is still unknown. The objective of this study was to investigate whether the Notch pathway is related to injuries actinic cheilitis and squamous cell carcinoma of the lip and participation in oral photocarcinogenesis. For this, were used 45 cases of actinic cheilitis, 15 cases of squamous cell carcinoma of the lip and lip 05 cases with normal aspect in which we analyzed the expression of Notch1 and Jagged1 by immunohistochemistry. The results showed loss of Notch1 expression in 40% of squamous cell carcinomas of the lip, suggesting that reduced expression of Notch1 can convert to an activated keratinocytes and immature state. There was also a difference in labeling patterns of Notch 1 and Jagged1 epithelial cells suggesting that the Notch pathway signal is transmitted from an apical cell to a basal cell due to localization of cells expressing the receptor and expressing the ligand. In summary, the immunohistochemical results do not show a differential regulation of Notch 1 and Jagged1 expression in UV induced lesions.
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Hofmann, Jennifer Jean. "Notch signaling in vascular development the roles of notch 1 and jagged 1 in vessel morphogenesis and disease /." Diss., Restricted to subscribing institutions, 2009. http://proquest.umi.com/pqdweb?did=1925779381&sid=21&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Lehar, Sophie M. "Tuning Notch signals in T cell development /." Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/8356.
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Moretti, Julien. "Déubiquitinations dans la voie de signalisation Notch." Phd thesis, Université Pierre et Marie Curie - Paris VI, 2011. http://tel.archives-ouvertes.fr/tel-00726110.
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La signalisation Notch est une voie extrêmement conservée depuis Caenorhabditis elegans jusqu'aux mammifères en passant par Drosophila melanogaster. Elle est requise dès le développement embryonnaire et contrôle de nombreux processus comme la différenciation et le choix du destin cellulaire, la prolifération, ou encore le maintien de stocks de cellules souches et l'apoptose. La voie est basée sur l'activité du récepteur Notch, un hétérodimère transmembranaire qui est activé lors de contacts intercellulaires par la liaison de ses ligands qui sont également des protéines transmembranaires. Suite à cette activation, le récepteur subit une série de deux clivages protéolytiques internes, respectivement catalysés par une métalloprotéase ADAM et par le complexe multi-protéique γ-secrétase. Ce dernier clivage libère le domaine intracellulaire de Notch dans le cytoplasme, cette forme étant ensuite transportée dans le noyau où elle active directement la transcription des gènes cibles de la voie Notch en se liant à ses co-facteurs de transcription, CSL et Mastermind. Le récepteur Notch est régulé à diverses étapes par des processus d'ubiquitination : la monoubiquitination du récepteur Notch activé contrôle son clivage γ-secrétase, la polyubiquitination du récepteur Notch non activé et endocytosé contrôle sa dégradation dans les lysosomes. Les processus d'ubiquitination sont réversiblement contrôlés par la déubiquitination. Or, aucune déubiquitination n'a été identifiée dans la voie de signalisation Notch. Mon projet consistait à identifier les déubiquitinases - les enzymes responsables de la déubiquitination - impliquées dans les deux processus d'ubiquitination décrits précédemment. Nous avons pour cela mis au point deux cribles en immunofluorescence permettant de tester une banque de shRNA qui cible l'expression des 91 déubiquitinases connues ou putatives du génome humain. Le premier crible m'a permis d'identifier eIF3f, une sous-unité du facteur d'initiation de la traduction eIF3, comme une nouvelle protéine portant une activité déubiquitinase. eIF3f est recrutée au récepteur Notch via l'E3 ubiquitine ligase Deltex, et régule positivement la voie de signalisation Notch en déubiquitinant le récepteur Notch activé avant le clivage γ-secrétase, favorisant ainsi la production de la forme transcriptionnellement active de Notch. Par ailleurs, le deuxième crible a identifié plusieurs déubiquitinases candidates, dont le rôle dans la régulation du trafic intracellulaire du récepteur Notch non activé est en cours de validation.
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Beatus, Paul. "Molecular diversity in the Notch receptor family /." Stockholm : Karolinska Univ. Press, 2001. http://diss.kib.ki.se/2001/91-89428-20-x/.
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Davati, Soheil. "VLSI implementation of recursive digital notch filter." Ohio : Ohio University, 1986. http://www.ohiolink.edu/etd/view.cgi?ohiou1183128831.
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Collins, S. M. "Notch targets in the Drosophila hematopoietic system." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597869.
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Expression arrays and chromatin immunoprecipitation in a Drosophila blood cell line had previously identified high confidence direct targets of Notch signalling. Therefore one aim of the research was to validate a selection of these putative Notch targets. These were shown to contain Notch responsive enhancers that direct expression in the lymph gland, implicating these novel targets in blood cell regulation. Further analysis of two of these novel Notch targets, hindsight (hnt) and klumpfuss (klu) indicate that their expression overlaps with a known crystal cell-lineage marker, lozenge (lz). This suggests that these, and most likely the other targets, are involved downstream of Notch in precursor cells during crystal cell specification, as part of the gene cascade that results in terminal differentiation. My work has found that hnt and klu are both necessary for crystal differentiation, acting downstream of Notch and Lz. Furthermore, klu is sufficient to induce crystal cell fates in cells of another lineage. My work further suggests that Notch and Lz act in a co-ordinate manner. The model that emerges is that expression of lz confers competence to receive the Notch signal, so that the receiving cells activate genes required to promote crystal cell differentiation, including hnt and klu. The requirement of Notch and Lz in Drosophila hematopoiesis echo that of NOTCH1 and the homologue of Lz, Runx1, in the mammalian system, suggesting that novel targets identified here may be relevant to the regulatory networks involved in mammals.
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Johnson, R. I. "Intersections between Notch signalling and planar polarity." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.605640.
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Planar polarity refers to the organisation of cells within the plane of the epithelium. In the Drosophila eye this is manifest in the chirality of the asymmetrical ommatidia determined by the specification of the R4 photoreceptor, and by the direction in which the ommatidia rotate during development. Genes involved in conferring appropriate planar polarity include frizzled and dishevelled. Frizzled is required in the R3/R4 photoreceptor precursors for ommatidia to correctly interpret polarity and mutations in frizzled and dishevelled subsequently affect the allocation of the R3 and R4 fates because Notch signalling, which is required to specify the R4 fate, is aberrant. The role that several genes implicated in planar polarity have in regulating Notch activity in this fate decision has been investigated using the Notch responsive enhancer md0.5 as an assay. One widely accepted model proposes that the Rac/Rho GTPases, the STE-20 like kinase Misshapen, and components of the JNK cascade transduce a polarity signal downstream of Frizzled to upregulate transcription of the Notch ligand Delta. Evidence presented here indicates that these factors are not essential to regulate Notch activity in this tissue and that regulation of the ligands is not critical for introducing a bias in Notch activity in this cell fate. An alternative model is proposed in which asymmetrical localisation of several core polarity proteins results in asymmetrical activation of N across the R3/R4 cell boundary. This is based on the observation that a number of genes are essential for normal Notch signalling. Frizzled is required in the R3 precursor and localises to the membrane abutting the R4 cell at the time when Notch activity between these cells is resolved in an equatorial to polar direction.
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Tay, Joyce Z. Y. "Structural Studies Of Notch And Its Ligands." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504619.
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Oon, Chern. "Role of Notch ligands in tumour angiogenesis." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:cb237fdd-e532-406c-808b-8092257968c2.
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The well conserved Notch signalling pathway plays a crucial role in vascular development and physiology. Delta-like 4 (DLL4) and Jagged1 (JAG1) are two key notch ligands implicated in angiogenesis. Both ligands were shown to have opposite effects on vasculature. DLL4-Notch signalling inhibits sprouting resulting in fewer but better perfused blood vessels, promoting tumour growth. In contrast to DLL4, very little is known about JAG1- Notch signalling in tumour angiogenesis and its influence on tumour growth and progression. The overall aim of this work is to study the functional difference between DLL4 and JAG1-Notch signalling. The effects of murine DLL4 and murine JAG1 over-expression on tumour growth and angiogenesis was also investigated in a mouse U87 xenograft model. Firstly, the downstream target genes of DLL4 and JAG1-Notch signalling were established through microarray and QPCR. Angiogenic assays such as sprouting, network formation and migration assays were employed to study the functional effects of these two ligands in endothelial cells. The thesis firstly demonstrates that JAG1 has opposing effects on endothelial cells compared to DLL4 by increasing sprout coverage and network formation. JAG1 is less potent than DLL4 in stimulation of Notch target genes in primary endothelial cell (HUVEC) but both displayed equal potency in HMEC-1, an immortalised endothelial cell line. The growth of U87 cell lines which over-expressed murine DLL4 or murine JAG1 was slower compared to wild-type U87 cell line in vitro. JAG1- and DLL4- Notch signaling have different effects on vessel formation, which impacted on the tumour growth in vivo. Interestingly, tumours over-expressing mDLL4 had less but larger vessels compared to control, whereas mJAG1 produced more yet functional vessels; both tumours had significantly reduced pericyte coverage. Both U87 mDLL4 and mJAG1 over-expressing tumours showed increased resistance towards anti-VEGF therapy, compared to control tumours. Sensitivity to therapy was restored in combinational treatment with DBZ and bevacizumab. The mechanism behind the differential responsiveness of the Notch receptors to DLL4 or JAG1 ligands could either reflect modulation by fringes, a family of glycosyltransferases that regulate Notch signalling or by a positive feedback loop present for DLL4-Notch signalling only. Fringe was found to be abundantly expressed in endothelial cells and highly vascularised tumours. This work has highlighted some key novel differences between the two Notch Ligands.
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Murta, Daniel José de Moura Carita Dinis. "Notch signaling, genital remodeling and reproductive function." Doctoral thesis, Universidade de Lisboa. Faculdade de Medicina Veterinária, 2014. http://hdl.handle.net/10400.5/6889.
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Tese de Doutoramento em Ciências Veterinárias. Especialidade de Ciências Biológicas e BiomédicasThe objective of this thesis is to evaluate the association between Notch signaling, genital cellular remodeling and reproductive function, in the mouse model. Five experimental chapters are included in this thesis. In experiments 1 and 2, we evaluated transcription and expression patterns of Notch component and effector genes in testis post-natal development, along the spermatogenic cycle and the epididymis. In experiment 3, we evaluated the male reproductive phenotype of in vivo Notch blockade by DAPT. In experiments 4 and 5 we evaluated transcription and expression patterns of Notch component and effector genes in the ovary, oviduct and uterus along the estrous cycle. Results indicate that Notch signaling is active and associated to male and female genital cellular remodeling. In the male, results prompt for a regulatory role of Notch signaling in spermatogonia pool maintenance, onset of spermatogenesis, in the pace of the spermatogenic cycle, germ cell identity, and epididymis spermatozoa maturation. In the female, results prompt for a regulatory role in ovarian follicle and corpus luteum development, and oviduct and uterus epithelial cell turnover and function. Notch signaling is operating in the testis and ovarian cellular interstitium, and in luminal and glandular epithelia of genital tract, probably regulating intercellular communication.
RESUMO - A via de sinalização Notch, remodelação celular genital e a função reprodutiva. - Esta tese avalia a relação entre a via de sinalização Notch, o remodelação celular genital e a função reprodutiva, sendo constituída por cinco capítulo experimentais. Nos dois primeiros, avaliamos o padrão de transcrição e expressão dos componentes e efectores da via Notch no desenvolvimento testicular pós-natal, ao longo do ciclo espermático e no epidídimo. Na experiência 3, avaliamos o fenótipo reprodutivo masculino decorrente do bloqueio in vivo da via Notch por DAPT. Nas experiências 4 e 5 analisamos o padrão de transcrição e de expressão dos componentes e efectores da via Notch no ovário, oviduto e no útero ao longo do ciclo éstrico. Os resultados indicam que a via Notch está activa e associada à remodelação genital masculino e feminino. No macho, os resultados apontam-lhe um papel regulador na manutenção do pool de espermatogónias, no início da espermatogénese, na coordenação do ciclo espermático, na identidade celular germinal, e na maturação espermática. Na fêmea, os resultados apontam para um papel regulador no desenvolvimento folicular e do corpo lúteo, e na função e ciclicidade do oviduto e útero. A via Notch opera no interstício celular do testículo e do ovário, e no epitélio luminal e glandular do tracto reprodutivo, regulando a comunicação intercelular.
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Jones, Matthew Leslie. "The subnuclear localisation of Notch responsive genes." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/274909.
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Title: The subnuclear localisation of Notch responsive genes. Candidate Name: Matthew Jones Notch signalling is a highly conserved cell-cell communication pathway with critical roles in metazoan development and mutations in Notch pathway components are implicated in many types of cancer. Notch is an excellent and well-studied model of biological signalling and gene regulation, with a single intracellular messenger, one receptor and two ligands in Drosophila. However, despite the limited number of chemical players involved, a striking number of different outcomes arise. Molecular studies have shown that Notch activates different targets in different cell types and it is well known that Notch is important for maintaining a stem cell fate in some situations and driving differentiation in others. Thus some of the factors affecting the regulation of Notch target genes are yet to be discovered. Previous studies in various organisms have found that the location of a gene within the nucleus is important for its regulation and genome reorganisation can occur following gene activation or during development. Therefore this project aimed to label individual Notch responsive loci and determine their subnuclear localisation. In order to tag loci of interest a CRISPR/Cas9 genome-editing method was established that enabled the insertion of locus tags at Notch targets, namely the well-characterized Enhancer of split locus and also dpn and Hey, two transcription factors involved in neural cell fate decisions. The ParB/Int system is a recently developed locus tagging system and is not well characterised in Drosophila. It has a number of advantages over the traditional LacO/LacI-GFP locus tagging system as it does not rely on binding site repeats for signal amplification and can label two loci simultaneously in different colours. This thesis characterised the ParB/Int system in the Drosophila salivary gland and larval L3 neuroblast. Using 3D image segmentation hundreds of nuclei were reconstructed and a volume based normalisation method was applied to determine the subnuclear localisation of several Notch targets with and without genetic manipulations of the Notch pathway.
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Moretti, Julien. "Deubiquitinations dans la voie de signalisation Notch." Paris 6, 2011. http://www.theses.fr/2011PA066365.
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La signalisation Notch est une voie extrêmement conservée, requise dès le développement embryonnaire et contrôlant le choix du destin cellulaire au cours de nombreux processus. Elle est basée sur l’activité du récepteur transmembranaire Notch qui est activé lors de contacts intercellulaires par ses ligands également transmembranaires. Le récepteur subit alors deux clivages protéolytiques, par une métalloprotéase ADAM puis par le complexe multi-protéique γ-secrétase, qui libèrent le domaine intracellulaire de Notch dans le cytoplasme, forme qui est ensuite transportée dans le noyau où elle active la transcription de ses gènes cibles. Le récepteur Notch est régulé par divers processus d’ubiquitination : la monoubiquitination du récepteur Notch activé contrôle son clivage γ-secrétase, la polyubiquitination du récepteur Notch non activé contrôle sa dégradation lysosomiale. L’ubiquitination est réversiblement contrôlée par la déubiquitination. Or, aucune déubiquitination n’a été identifiée dans la voie de signalisation Notch. Mon projet consistait à identifier les déubiquitinases – enzymes catalysant la déubiquitination – impliquées dans les deux processus d’ubiquitinationde Notch, en utilisant deux cribles permettant de tester une banque de shRNA qui cible l’expression des 91 déubiquitinases humaines. Le premier m’a permis d’identifier eIF3f, une sous-unité du facteur d’initiation de la traduction eIF3, comme une nouvelle déubiquitinase qui agit sur Notch activé avant le clivage γ-secrétase. Par ailleurs, le deuxième crible a identifié plusieurs candidates, parmi lesquelles USP12 dont le rôle dans la régulation du trafic de Notch non activé est en cours de validation
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Edwards, Robert Tyler. "Performance of a Biomimetically Inspired Notch Design." University of Dayton / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1462039449.
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Hernandez, de Madrid Diaz Beatriz. "Structural basis of serrate regulation of Notch." Thesis, University of Manchester, 2009. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.518890.
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Laddada, Lilia. "Etude du développement des tendons et de leur interaction avec les précurseurs de muscles lors de la myogenèse appendiculaire chez la Drosophile." Thesis, Université Clermont Auvergne (2017-2020), 2018. http://www.theses.fr/2018CLFAC011/document.
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La mise en place du système musculo-(exo)squelettique de la drosophile est un modèle d’organisation particulièrement propice à l’étude des interactions tissulaires au cours du développement.Notre étude vise à, d’une part, comprendre la myogenèse appendiculaire à travers l’étude des interactions précoces entre les précurseurs de tendon et les myoblastes, et d’autre part, étudier les mécanismes de différenciation des précurseurs de tendons associés au disque de patte. Dans ce contexte nous avons adapté la méthode GRASP (GFP Reconstitution Across Synaptic Partners) ainsi que l’imagerie en temps réel à notre modèle pour démontrer l’existence des interactions cellulaires entre les précurseurs de tendons et les myoblastes, nous avons aussi mis au point une approche cellule-spécifique afin de trier les précurseurs de tendons et les myoblastes associés au disque de patte, ce qui nous a permis d’obtenir dans un premier temps les données transcriptomiques des précurseurs de tendons. J’ai également étudié l’impact de l’altération des précurseurs de tendon sur le comportement des myoblastes associés et inversement. Nos résultats montrent que l’altération du développement des tendons entraîne une désorganisation spatiale des myoblastes environnants. Dans la seconde partie de mon projet, je me suis intéressée à l’implication de la voie Notch et des gènes de la famille odd-skipped dans la différenciation et la morphogenèse des précurseurs de tendon. J’ai ainsi démontré que Notch est nécessaire et localement suffisant pour induire l’expression de stripe et que les gènes odd-skipped et stripe coopèrent en aval cette voie pour permettre l’invagination et l’élongation sous forme de tube des longs tendons internes de la patteThe formation of the musculo-(exo)skeletal system in drosophila is a remarkable example of tissue patterning making it a suitable model for studying multiple tissue interactions during development.The aim of our study is to better understand appendicular myogenesis through the identification of early interactions between tendon and muscle precursors, and by investigating the mechanisms governing the specification of tendon cell precursors of the leg disc. In order to characterize the interaction between these two tissues, we adapted the GRASP method (GFP Reconstitution Across Synaptic Partners) and set up live imaging experiments to reveal cellular interactions between tendon precursors and myoblasts. We have also conducted a genome wide cell-specific analysis using Fluorescence-activated cell sorting (FACS) on imaginal discs which allowed us to perform a tendon cell specific transcriptional analysis.To test whether reciprocal muscle-tendon interactions are necessary for correct muscle-tendon development, I performed experiments to specifically interfere with the development of tendon or muscle precursors. By altering tendon precursors formation during the early steps of leg development, we affect the spatial localization of the associated myoblasts. These findings provide the first evidence of the developmental impact of early interactions between muscle and tendon precursors in the leg disc.In the second part of my project, I investigated the role of Notch pathway and odd-skipped genes in the differentiation and morphogenesis of tendon precursors. Thus, I have demonstrated that Notch signalling pathway is necessary and locally sufficient for the initiation of stripe expression, and that both odd-skipped genes and stripe are required downstream of Notch to promote morphological changes associated with formation of long tubular tendons
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Boroumand, Soulmaz. "Investigating the epidermal Notch activation during wound healing and the consequences of prolonged Notch activity during skin wound healing." Thesis, Durham University, 2014. http://etheses.dur.ac.uk/10785/.
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The Notch signaling pathway is critically involved in cell fate decisions during skin development and homeostasis. In the present study an in vivo model (seven-week-old male, C57BL/6) was used to elucidate the role of epidermal Notch activation in the healing of full-thickness dermal wound. Immunolocalization of activated Notch1, Notch2 and Jagged1 was performed during skin wound healing in vivo in mice. The expression level of Notch1, Notch 2 and Jagged1 in the C57BL/6 skin was examined by quantitative PCR (qPCR). This study shows that skin injury rapidly actives Notch signaling in the epidermis. Epidermal forced Notch1 activation results in a Jagged1 dependent Notch2 activation in epidermis. Data presented in this thesis also demonstrate that the prolonged epidermal Notch activation via a 4-hydroxy-tamoxifen-inducible transgene before and after wounding caused an over-activation of Notch during early stages of the healing of full-thickness dermal wounds. The expression level of Notch1, Notch2 and the inflammatory Notch related genes, in the transgenic wounded skin was examined by quantitative PCR (qPCR). The phenotypes and morphology of the transgenic skin were compared with that of wild type (WT) controls. The skin response to wound healing was studied by H&E staining at the microscopic level at 2, 5 and 8 days post injury. These data show that the prolonged epidermal Notch activity may do more harm than good in terms of an increased inflammatory response at the wound site. These data suggest that Notch plays an important role in the early stages of the skin wound healing process, a finding that has implications in wound inflammatory responses. This thesis also examines skin wound healing in different anatomical locations on seven-week-old male, C57BL/6 mice model. 4mm full thickness dermal wounds were made at different anatomic regions; upper posterior, middle to posterior and posterior-most (caudal). These data showed that lower body wounds healed significantly better than those in the upper posterior, or middle to posterior of the mouse back skin. The data presented here show that anatomical location is important in wound healing responses, as reflected by differences in keratinocyte proliferation and differentiation.
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Kobia, F. M. "TARGETING NOTCH TRAFFICKING IN HUMAN CANCER CELLS: A. PHARMACOLOGIC INHIBITION OF THE VACUOLAR H+ ATPASE REDUCES PHYSIOLOGIC AND ONCOGENIC NOTCH SIGNALING. B. HIGH CONTENT SCREEN FOR NOVEL MODULATORS OF THE NOTCH PATHWAY." Doctoral thesis, Università degli Studi di Milano, 2016. http://hdl.handle.net/2434/365255.
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Notch signaling is prominently involved in cell fate decision and growth regulation in metazoan tissues. Because of this, Notch is often upregulated in cancer and current efforts point to developing drugs that block its activation. Notch receptor endocytosis towards acidic compartments is a recently appreciated determinant of signaling activation. The Vacuolar H+ ATPase (V-ATPase) is responsible for acidification of endocytic organelles and recently it has been shown that mutants in V-ATPase subunit encoding genes in model organisms display loss of Notch signaling phenotypes. In the first part of my graduate studies, we aimed at discovering whether pharmacologic reduction of V-ATPase activity affected Notch signaling. We found that administration of BafilomycinA1 (BafA1), a highly specific V-ATPase inhibitor decreases Notch signaling during Drosophila and Zebrafish development, and in human cells in culture. In normal breast cells, we have found that BafA1 treatment leads to accumulation of Notch in the endo-lysosomal system, and reduces its processing and signaling activity. In Notch-addicted breast cancer cells, BafA1 treatment reduces growth in cells expressing membrane tethered forms of Notch, while sparing cells expressing cytoplasmic forms. In contrast, V-ATPase inhibition reduces growth of leukemia cells, without affecting Notch activating cleavage. However, consistent with the emerging roles of V-ATPase in controlling multiple signaling pathways, in these cells Akt activation is reduced, as it is also the case in BafA1-treated breast cancer cells. Our data support V-ATPase inhibition as a novel therapeutic approach to counteract tumor growth sustained by signaling pathways regulated at the endo-lysosomal level.
The functions of Notch throughout the life of an individual are varied and complex. This complexity is not sufficiently accounted for by the limited core of known Notch signaling components and a growing body of evidence attributes it to additional factors that determine whether, when and how Notch functions within a given context. Considering this, in the second part of my graduate work, we sought to identify novel genes that might influence Notch. Thus, we performed a high content immunofluorescence-based RNA interference screen of a pharmacologically-relevant subset of the human genome. To this end, we monitored how knockdown of specific genes perturbs the localization of the Notch-1 receptor in human breast cells under resting and signaling conditions. Here we present the screen setup, the primary screen results and the candidate follow-up strategy.
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Oltmann, Meredith Leigh. "Disruption of the furin cleavage site in mouse Notch 1 results in cardiovascular malformations due to hypomorphic Notch 1 signaling." Diss., Restricted to subscribing institutions, 2009. http://proquest.umi.com/pqdweb?did=1872078271&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Shaw, Benjamin. "Function and evolution of the atypical Notch ligands Dlk1 and Dlk2 during vertebrate development." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/271791.
Full textAbstract:
Delta-like homologue 1 (Dlk1) and Dlk2 encode vertebrate-specific transmembrane proteins belonging to the Jagged/Delta/Serrate family of Notch ligands. Murine Dlk1 is widely expressed during embryonic development and targeted deletion results in defects in numerous developmental processes, such as adipogenesis, haematopoiesis, neurogenesis and skeletal muscle formation. However, the mechanisms by which DLK1 regulates these processes remains unclear. The purpose of this project is to examine the function of these genes using zebrafish as an in vivo model, allowing insight to the ancestral functions of these genes. We have strong evolutionary evidence that dlk2 is the ancestral version of the gene from which dlk1 is derived; therefore, the thesis focuses primarily on the role of dlk2 in the zebrafish system. I initially examine the expression of zebrafish dlk1 and dlk2 during embryonic development and in the adult brain, determining similarities and differences between mouse and zebrafish. In particular, dlk1 and dlk2 in the fish exhibit a pattern that is more reminiscent of Dlk2 in the mouse. This developmental expression pattern is essential for the interpretation of the modulation of Dlk2 in later chapters, and is aided by the generation of a mammalian Dlk2 antibody that cross-reacts with zebrafish. We obtained a dlk2 mutant and used this line to examine the role of the DLK2 protein in development and in the adult brain. I demonstrate that, in the absence of DLK2, a population of neural precursor cells appear to over-proliferate early in zebrafish development. Later, by larval stages, these cells are absent, suggesting a premature activation and subsequent depletion of the progenitor cell pool in the mutant, reminiscent of the Dlk1 mutant in mouse. Associated with this phenotype are larval behavioral defects in motor response. In this thesis, it will be shown that in the adult dlk2 mutant zebrafish, the radial glial cell population in the telencephalon is completely depleted. These radial glial cells are thought to be responsible for adult neural regeneration in zebrafish, and our characterization of a mutant completely lacking this cell population provides a rich model to further examine and understand the functions of this well-studied but poorly understood cell population. These findings have both functional and evolutionary implications for the relative roles of these two vertebrate specific atypical Notch ligands.
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Masià, Fontana Anna. "El papel de la vía Notch en Rabdomiosarcoma." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/121513.
Full textAbstract:
El Rabdomiosarcoma (RMS) es el tumor de partes blandas más común en la infancia. Los pacientes con enfermedad diseminada continúan teniendo un mal pronóstico a pesar del uso de terapias intensivas. En este trabajo se evidencia la expresión y activación notable de la vía Notch en RMS y se demuestra la implicación de la vía como elemento clave en la regulación de mecanismos de adhesividad, movilidad e invasividad en células de RMS. Además se propone un mecanismo de regulación de estos procesos, mediado por Notch, a través de la regulación positiva de varias moléculas de adhesión, tales como la N-Caderina e Integrina-α9. Así mismo, se describen los efectos observados de la inhibición de la vía Notch in vivo y se profundiza en la caracterización del estado muscular inmaduro propio del RMS según los niveles de expresión de varios genes claves para el proceso de la miogénesis, tales como la vía Notch, la N-Caderina y la Integrina-α9 en un amplio abanico de tumores de RMS.Rhabdomyosarcoma (RMS) is the commonest type of soft-tissue sarcoma in children. Patients with metastatic RMS continue to have very poor prognosis. This work provides evidence of Notch pathway expression and activation in RMS and it demonstrates a critical role of the Notch pathway in the activation of the process that leads to cell mobility and invasiveness in RMS cells. Furthermore N- cadherin and α9-integrin are postulated as leading actors in the association between the Notch pathway and promotion of cell adhesion, motility and invasion, pointing to these proteins and the Notch pathway itself as interesting putative targets for new molecular therapies against metastases in RMS. It also describes the observed effects of the inhibition of the Notch pathway in vivo.
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Guiu, Sagarra Jordi 1983. "Notch activation and downstream targets in embryonic hematopoiesis." Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/98475.
Full textAbstract:
La regió de l’aorta-gonada-mesonefros (AGM) és el primer nínxol de les
cèl·lules mare hematopoètiques. Està descrit que la via de Notch és necessària
per generar artèries i cèl·lules mare hematopoètiques. Les cèl·lules mare
hematopoètiques es generen a partir de les artèries durant el desenvolupament
embrionari. Tenint en compte que els vasos arterials es formen abans que les
cèl·lules mare hematopoètiques, durant molt temps ha estat controvertit si la via
de Notch només indueix la formació d’artèries i en canvi l’abscència de cèl·lules
mare hematopoètiques és un efecte secundari o si per contra, la via de Notch
participa activament en la inducció d’ambdós programes genètics, l’arterial i
l’hematopoètic. Moltes de les funcions descrites de la via de Notch són
conseqüència de l’expressió de les seves dianes transcripcionals: Hes i Hesrelated
(Hrt). No obstant cada cop s’estan identificant noves dianes
transcripcionals de la via de Notch que són específiques de teixit.
En aquesta tesis doctoral, demostrem que l’activació de la via de Notch per part
del lligand Jagged1 és necessària per activar el programa hematopoètic però
no cal per establir el programa arterial. Aquest fet demostra que la via de Notch
juga un paper clau i directe en l’hematopoèsi embrionaria. Per sota de la via de
Notch mostrem que els embrions deficients en Hes1 i Hes5 mantenen intacte el
programa arterial. Cal remarcar que també generen més quantitat de cèl·lules
mare hematopoètiques però que no són funcionals. A més tal mutants, tenen
nivells més alts d’expressió dels gens Runx1, Myb i Gata2; els quals són
importants reguladors de l’hematopoèsi. Per acabar demostrem que Notch
activa la transcripció de Gata2 i que HES-1 l’inhibeix. Això genera un
Incoherent Feed-Fordward loop, el qual regula estretament els nivells de Gata2
necessàris per generar cèl·lules mare hematopoètiques.The aorta-gonad-mesonephros (AGM) is the first Hematopoietic Stem Cell (HSC) niche. It was previously shown that Notch pathway is required to induce the arterial fate as well as to generate Hematopoietic Stem Cells. HSC emerge at the site of arterial vessels during embryonic development. Since arterial fate precedes HSC generation, it has long been controversial whether Notch exclusively induces the arterial program and the lack of HSC is a secondary defect; or Notch is directly involved in activating both genetic programs, arterial and hematopoietic. The best-characterized Notch targets are Hes and Hesrelated genes (Hrt) since they are involved in most of described Notch functions, however there is a growing number of tissue-specific transcriptional Notch-targets. In this thesis, we found that Jagged-mediated activation of Notch is required for the correct execution of the definitive hematopoietic program but not for the establishment of the arterial fate, thus demonstrating that Notch exerts a specific hematopoietic function in the embryo. Downstream of Notch pathway, we also show that embryos deficient for Hes1 and Hes5 alleles contain an intact arterial program but produce increased numbers of non-functional hematopoietic stem cells associated to higher levels of the hematopoietic regulators Runx1, Myb and Gata2. Moreover, Gata2 transcription is positively regulated by Notch and negatively controlled by HES-1. This creates an incoherent feed-forward loop that tightly controls Gata2 levels to generate HSC.