Dissertations / Theses on the topic 'Resistance and agency'
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Lim, Julia Alison. "Resistance and agency in Bharati Mukherjee's Wife, the Tiger's Daughter and Jasmine /." Title page, contents and preface only, 2000. http://web4.library.adelaide.edu.au/theses/09AR/09arl7323.pdf.
Full textPascucci, Elisa. "Beyond depoliticization and resistance : refugees, humanitarianism, and political agency in neoliberal Cairo." Thesis, University of Sussex, 2014. http://sro.sussex.ac.uk/id/eprint/51440/.
Full textNordlander, Andrea. "Agency, Resistance and Embodiment in The Context of PMS : a Qualitative Study." Thesis, Linköpings universitet, Tema Genus, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-145628.
Full textJeffery, Susan Elizabeth. "Resistance, religion and identity in Ojitlan, Oaxaca, Mexico." Thesis, Durham University, 2001. http://etheses.dur.ac.uk/3960/.
Full textGoode, Jackie. "Governmentality : welfare, health and higher education as sites of agency, resistance and identity." Thesis, University of South Wales, 2007. https://pure.southwales.ac.uk/en/studentthesis/governmentality-welfare-health-and-higher-education-as-sites-of-agency-resistance-and-identity(6eb9fc1a-f35f-491b-a049-bb5f0b9186c6).html.
Full textLo, Wai Han. "Inter-discursive strategies, resistance and agency the case of poverty in Hong Kong media." HKBU Institutional Repository, 2015. https://repository.hkbu.edu.hk/etd_oa/210.
Full textBanerjee, Supurna. "Nurturing resistance : agency and activism of women tea plantation workers in a gendered space." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9837.
Full textTov??as, de Plaisted Blanca History & Philosophy Faculty of Arts & Social Sciences UNSW. "Resistance and cultural revitalisation: reading Blackfoot agency in the texts of cultural transformation 18701920." Publisher:University of New South Wales. History & Philosophy, 2007. http://handle.unsw.edu.au/1959.4/43907.
Full textSims, Maria A., Timothy J. Dennehy, Amanda Patin, Yves Carrière, Yong-Biao Liu, Bruce Tabashnik, Larry Antilla, and Mike Whitlow. "Arizona's Multi-agency Resistance Management Program for Bt Cotton: Sustaining the Susceptibility of Pink Bollworm." College of Agriculture, University of Arizona (Tucson, AZ), 2001. http://hdl.handle.net/10150/211325.
Full textMallick, Bhaswar. "Agency of Labor Resistance in Nineteenth Century India: Significance of Bulandshahr and F.S. Growse’s Account." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543581416769978.
Full textQuadrelli, Carol A. "Aberrance, Agency and Social Constructions of Women Offenders." Queensland University of Technology, 2003. http://eprints.qut.edu.au/15849/.
Full textLimaverde, Cabral Pinheiro David. "Pedagogies and Poetics of Agency: A Narrative Inquiry on Embodied Strategies in a Culture of Resistance." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/455150.
Full textO presente projeto está inserido em uma abordagem transdisciplinar, com foco em caminhos de como a Pedagogia Cultural é performada entre artistas da cidade de Fortaleza, Brasil - no contexto de agênciamentos socialmente construídos e incorporizados. Através das narrativas desses artistas, timelines cartográficas e envolvimento experiencial com os sujeitos, este projeto tem como objetivo: 1) Compreender como a pedagogia se insere na construção social e incorporização das formas de agenciamento de artistas de Fortaleza, com um possível conteúdo e poética da resistência. 2) Criar um diálogo entre as categorias de Pedagogia Cultural, Resistência, Agenciamento e Embodiment. 3) Levantar possíveis interrogantes / conexões através das ricas narrativas fornecidas pelos dez artistas / sujeitos. Como performer, educador e pesquisador, o autor coloca-se, também, como sujeito, explorando a relação entre as categorias de investigação, suas próprias experiências (em práticas físicas e criativas) e as narrativas de dez artistas retratadas como possuindo um engajamento de conteúdo social e/ou político em suas poéticas. Além disso, sob uma abordagem fenomenológica, esta pesquisa desenvolve o conceito de Vontade Como Desejo Social e introduz linhas de raciocínios de aprendizagem sobre Agenciamentso em Movimento e Propriocepção.
El presente proyecto se inserta en una perspectiva transdisciplinaria, con enfoque en caminos de cómo la Pedagogía Cultural es performada entre los artistas de la ciudad de Fortaleza, Brasil – en el contexto de agencias socialmente construidas y corporizadas. A través de narrativas venidas de eses artistas, timelines cartográficas y la participación experiencial con los sujetos, este proyecto tiene como objetivo: 1) Comprender cómo la pedagogía se inserta en la construcción social y la corporación de las formas de agencia de los artistas de Fortaleza, con un posible contenido y poética de resistencia. 2) Crear un diálogo entre las categorías de Pedagogía Cultural, Resistencia, Agencia y Embodiment. 3) Levantar posibles interrogantes / conexiones por las ricas narrativas colectadas de los diez artistas / sujetos. Como performer, educador e investigador, el autor también se inserta como sujeto, explorando una relación entre las categorías de investigación, sus experiencias (en practicas fisicas y creativas) y las narrativas de los artistas retratados como poseedores de un engajamento de contenido social y / o político en sus poéticas. Además, en una metodología fenomenológica, esta investigación desarrolla el concepto de Voluntad Como Deseo Social y líneas de raciocinio de aprendizaje sobre agencias en movimiento y propriocepción.
Ayele, Sehin Teferra. "Agency and sisterhood : a feminist analysis of Ethiopian sex workers' experiences of, and resistance to, violence." Thesis, SOAS, University of London, 2016. http://eprints.soas.ac.uk/23793/.
Full textAlvarado, Beatriz Rosa. "Issues of voice and agency in Andean rural young women's education an ethnographic study /." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1155670273.
Full textBobb-Smith, Yvonne. "I know who I am, a Caribbean woman's identity in Canada, agency and resistance in community organizing." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0024/NQ45809.pdf.
Full textCarter, Frances Hannah. "Magic toyshops : narrative and meaning in the women's sex shop." Thesis, Kingston University, 2014. http://eprints.kingston.ac.uk/28758/.
Full textKoller, Kathrin. "'The Al Nebra Bedouin and the State of Israel : a Case Study of Forced Settlement, Agency and Resistance." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.517212.
Full textPourzand, Niloufar. "A tapestry of resistance : Afghan educated refugee women in Pakistan : 'agency', identity and education in war and displacement." Thesis, University of Greenwich, 2003. http://gala.gre.ac.uk/6271/.
Full textKöller, Kathrin. "The Al-Nebra Bedouin and the state of Israel : a case study of forced settlement, agency and resistance." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670002.
Full textVinson, Jenna Elizabeth. "Teenage Mothers as Rhetors and Rhetoric: An Analysis of Embodied Exigence and Constrained Agency." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/293424.
Full textde, Silva Kimaya. "A Journey to New Narratives: How Sri Lankan Migrant Women Challenge Perceptions through Resistance." Scholarship @ Claremont, 2017. http://scholarship.claremont.edu/cmc_theses/1561.
Full textRantakari, A. (Anniina). "Strategy as ‘dispositive’:essays on productive power and resistance in strategy-making." Doctoral thesis, Oulun yliopisto, 2016. http://urn.fi/urn:isbn:9789526213989.
Full textTiivistelmä Tämän väitöskirjan tarkoituksena on tutkia, kuinka valta tuottaa strategiatyötä organisaatioissa. Tutkimuksessani nojaudun Michel Foucault’n teoriaan vallasta tuottavana ja relationaalisena voimana. Tutkimukseni linssinä käytän Foucault’n dispositiivin käsitettä kahdesta syystä. Ensiksi, dispositiivin käsite mahdollistaa strategiaprosessi –ja käytäntötutkimuksen teoretisoinnin tavalla, joka yhdistää kolmen analyysielementin tarkastelun samanaikaisesti. Nämä analyysielementit ovat: valta, diskurssi ja subjektifikaatio. Toiseksi, dispositiivi mahdollistaa näiden kolmen elementin välisten suhteiden tarkastelun relationaalisesti ja prosessuaaliseesti. Tutkimukseni kontribuoi strategia prosessi- ja käytäntötutkimukseen tarkastelemalla strategiaa organisationaalisena dispositiivina. Määrittelen dispositiivin keinotekoiseksi rationaliteetiksi, jonka kautta vallan, diskurssin ja subjektiviteettien väliset suhteet tiivistyvät materiaalisiksi ja sosiaalisiksi käytännöiksi. Tämän kautta voin tarkastella kolmea keskeistä strategiatutkimukseen liittyvää ennakko-oletusta, joita ovat: strategia rationaalisena ja intentionaalisena suunnitteluna, strategin määrittelemistä strategian suunnittelu- ja implementointityöhon osallistumisen kautta, ja strategisen käytännön määrittelemistä ainoastaan strategian suunnittelemisen tai implementoinnin näkökulmasta. Tutkimuksen empirisessä osassa, joka on tapaustutkimus suomalaisesta puhelinpalvelukeskusta, osoitan kuinka osallistuminen strategiatyöhön tapahtuu valtasuhteessa organisationaalisen kontrollin ja yksilön itsensätoteuttamisen välillä. Tutkimuksen empiirinen osa lisää ymmärrystä kuinka strategiat realisoituvat valtasuhteiden kautta. Teoreettisen viitekehyksen ja empiirisen analyysin yhdistäminen mahdollistaa kolmen strategiatutkimukselle keskeisen prosessin tarkastelun uudesta näkökulmasta. Ensiksi, kuinka tehostettu strategian implementointi ja koherenssin tavoittelu voi johtaa konflikteihin ja strategiakäytäntöjen polarisoitumiseen, Toiseksi, kuinka strategian tulevaisuusorientoitunut suunnittelu voi johtaa menneisyyden käytäntöjen uudelleentuottamiseen. Kolmanneksi, kuinka resistanssi voidaan nahdä voimana, joka sekä tuottaa strategiatyötä että mahdollistaa strategin määrittelyn resistanssikäytäntöjen kautta
Aldrich, Debora Lynn Hill. "Heteroglossia and persuasive discourses for student writers and teachers: Intersections between out-of-school writing and the teaching of English." Diss., University of Iowa, 2014. https://ir.uiowa.edu/etd/5405.
Full textDemiri, Lirika. "Stories of Everyday Resistance, Counter-memory, and Regional Solidarity: Oral Histories of Women Activists in Kosova." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1524073114946126.
Full textWatts, Robert (Daud). "Rethinking Our Outlines/ Redrawing Our Maps: Representing African Agency in the Antebellum South 1783-1829." Diss., Temple University Libraries, 2011. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/212646.
Full textPh.D.
Rethinking Our Outlines/ Redrawing Our Maps: Representing African Agency in the Antebellum South 1783-1829 The lenses through which our common perceptions of African/Black agency in the antebellum period are viewed, synthetic textbooks and maps, rarely reveal the tremendous number of liberating acts that characterized the movements of Black people in the South from 1783 to 1829. During the American Revolution, 80,000 to 100,000 such enslaved Africans threw off their yokes and escaped their bondage. Subsequently, large numbers embarked on British ships as part of the Loyalist exodus from the United States, while others fled to the deep South, to Native lands, to the North, or held their ground right where they were, attempting, as maroons, to establish themselves and survive as free persons. While recent historical scholarship has identified many of the primary sources and themes that characterize such massive levels of proactivity, few have tried to present them as a synthetic whole. This applies to maps used to illustrate the African American history of those regions and times as well. Illustrating these movements defines the scope of this scholarly work entitled Rethinking Our Outlines/ Redrawing Our Maps: Representing African Agency in the Antebellum South 1783-1829. This work also critically looks at several contemporary maps of this period published in authoritative atlases or textbooks and subsequently creates three original maps to represent the proactive movements and relationships of Africans during this period.
Temple University--Theses
Kappler, Stefanie. "'Mysterious in content' : the European Union peacebuilding framework and local spaces of agency in Bosnia-Herzegovina." Thesis, University of St Andrews, 2012. http://hdl.handle.net/10023/2536.
Full textPhakathi, T. T. "Worker responses to work reorganisation in a deep-level gold mining workplace : perspectives from the rock-face." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:dac919be-8499-42b0-b560-8f4ea0dcdd50.
Full textKyriakides, Yvonne. "Art after Auschwitz : dimensions of ethics and agency in responses to genocide in post World War II art practice." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:9eb26a2a-13ed-42d6-80f1-e353c35c9d7f.
Full textLamond, Catherine. "Young people leaving care : plans, challenges and discourses." Thesis, University of Wolverhampton, 2016. http://hdl.handle.net/2436/621224.
Full textFaridpour, Arezoo, and Una Gutlic. "Att leda genom motstånd till förändring : En kvalitativ studie om ledarskap på Försäkringskassan." Thesis, Högskolan i Borås, Akademin för vård, arbetsliv och välfärd, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:hb:diva-15969.
Full textThe Swedish Social Insurance Agency (Försäkringskassan) has through the years aimed to support the social security system. The idea is that there should be assistance when needed, such as providing financial security in the event of illness, disability and for families with children. The vision behind this is a society where people can get a chance to feel secure even when life takes an unexpected turn. However, the Social Insurance Agency has received a lot of criticism about their management and their work has been questioned many times. Our aim with this qualitative study is to obtain a greater insight into the leadership of the Swedish Social Insurance Agency and how it is affected by change and resistance. Thus, we chose to interview six head of unit managers who work at the Swedish Social Insurance Agency where they were given the opportunity to speak freely through a semi-structured interview. We felt that this method was the most effective one in order to understand the meaning of leadership during changes and resistance. With the help of our theory, through our analysis, we could find that the managers perceive their leadership as transformative and that they perceive themselves as transformative leaders. We also came to the conclusion that their leadership style plays a major role in how they combat resistance that arises through changes within organizations. That is, how they have chosen to handle the changes and the oppositions in the organization. The result assured us that that unit managers have a lot in common regarding their leadership. The respondents used the same concepts such as communication, responsiveness and accessibility/availability to lead through resistance during change.
Fleeman, Renee. "Discovering Antibacterial and Anti-Resistance Agents Targeting Multi-Drug Resistant ESKAPE Pathogens." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6839.
Full textMaugendre, Maëlle. "Les réfugiées espagnoles en France (1939 - 1942) : des femmes entre assujettissements et résistances." Phd thesis, Université Toulouse le Mirail - Toulouse II, 2013. http://tel.archives-ouvertes.fr/tel-00961467.
Full textNurchayati, Nurchayati. "Foreign Exchange Heroes or Family Builders? The Life Histories of Three Indonesian Women Migrant Workers." Ohio University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1289411593.
Full textde, Graaf Kaitlyn. "Disciplining Women/Disciplining Bodies: Exploring how Women Negotiate Health and Bodily Aesthetic in the Carceral Context." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/26231.
Full textJönsson, Videsäter Kerstin. "Expression of multidrug resistance genes and proteins and effect of selenite in anthracycline-resistant human tumor cell lines /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-889-0/.
Full textMatsdotter, Henriksson Moa. "Papperslöst motstånd : Om strategier och praktiker i post-välfärdens marginaler." Thesis, Södertörn University College, School of Gender, Culture and History, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:sh:diva-2197.
Full textThe post-modern western city is going through two central changes in the organization of paid labour. One is the switch from production of goods to production of services, and the other is the increasing rift between well-paid labour with permanent jobs, and temporarily employed workers with low wages. Both of these processes are rasified and gendered, and strike harder against women, young persons and people of emigrant background. The flexible capitalism creates an informalization of the economy, breaking with earlier regulations of the labour markets, in which workers also need to find informal strategies in their individual and collective struggles. In this paper, I search for these “new” experiences of living and working in late capitalist society, by doing open interviews with three women of Latin-American origin, working without official permission (without documents) in the informal economy of Stockholm. Analyzing their narratives, I look for the agency and resistance that, according to my theoretical perspective, is part of everyday life of all suppressed subjects. I come to the conclusion that irregular systems of recruitment and other forms of interdependency could be useful for other groups of precarious workers. The interviewed women also use strategies such as fantasizing about a reversed world or focusing their thoughts on the future, and deceiving or avoiding the power(full), to cope with their everyday work situations and the contradictory class mobility they experienced in the migration. However, these strategies often reproduce an acceptance of power more than a resistance to it, and show us how the capitalism works as an hegemonic ideology incorporated in us all.
Price, Claire Emile. "Resistance to antimicrobial agents in bifidobacteria." Master's thesis, University of Cape Town, 2005. http://hdl.handle.net/11427/4323.
Full textFor bifidobacteria to survive and achieve colonisation, they have to interact with inhibitory host-produced substances such as bile salts. Another aspect which should be studied is the safety of the probiotic bacterium and risks of acquisition of genes for resistance to antimicrobial agents. Although bifidobacteria exhibit resistance to a wide range of antibiotics, little is known about the molecular basis for this resistance. The aim of this project was, therefore, to investigate the molecular mechanisms responsible for the resistance to antibiotics and bile salts observed in bifidobacteria, and more specifically, to determine whether efflux systems are involved in this resistance. Five Bifidobacterium spp. were exposed to a range of antimicrobial agents. These included ethidium bromide, the bile salt sodium glycocholate, and a range of antibiotics.
Picard, E. Kezia. "A radical relational agency : Foucault, complexity theory and environmental resistances." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11450/.
Full textColdman, Andrew James. "The development of resistance to anticancer agents." Thesis, University of British Columbia, 1986. http://hdl.handle.net/2429/26975.
Full textScience, Faculty of
Statistics, Department of
Graduate
Boyes, Alison. "Neo-Liberal Governance through Toronto Press Discourse on Youth Misconduct." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/19896.
Full textChung, Whasun Oh. "Macrolide resistance and its linkage to tetracycline resistance /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/9279.
Full textPurewal, Amarjit S. "Bacterial genetic determinants specifying resistance to cationic antimicrobial agents." Thesis, University of Hull, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.253168.
Full textO'Neill, Ciaran Francis. "Cellular mechanisms of sensitivity and resistance to platinum agents." Thesis, Institute of Cancer Research (University Of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324883.
Full textBendall, J. B. "Bacterial resistance to antimicrobial agents in geriatric medical wards." Thesis, University of Nottingham, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381441.
Full textJoseph-Horne, Tim. "Mechanisms of antifungal resistance in pathogenic fungi." Thesis, University of Sheffield, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387760.
Full textMin, Junxia. "Sphingolipid metabolic enzymes modulate anticancer drug resistance." Diss., Columbia, Mo. : University of Missouri-Columbia, 2006. http://hdl.handle.net/10355/5899.
Full textThe entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file viewed on (March 5, 2007) Vita. Includes bibliographical references.
Giske, Christian G. "Carbapenem resistance in Pseudomonas aeruginosa /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-080-0/.
Full textFrampton, Helen Kathleen. "Studies of resistance to Beta-lactam antibiotics in Bacillus licheniformis." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328977.
Full textIsmaeel, N. A.-A. "Resistance of Providencia stuartii to chlorhexidine and other antibacterial agents." Thesis, Cardiff University, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376556.
Full textO'Brate, Grupp Aurora Marie. "Anti-Microtube Agents: Mechanismes of Action and Resistance / Agents anti-microtubulars: mecanismes d'acció i resistència." Doctoral thesis, Universitat de Barcelona, 2005. http://hdl.handle.net/10803/686.
Full textMicrotubules (microtubules) are major dynamic structural components in cells that are essential for the development and maintenance of cell shape, cell signaling, movement, and division. We sought to understand the role microtubules play within the cellular context. Microtubules act as "active highways" within the cells and are essential for the correct operation of the cell by controlling the delivery, location, and function of a plethora of proteins. We have focused on the p53 and the HIF1-α proteins. Both these proteins are crucial players in tumor progression and angiogenesis. p53 is a tumor suppressor gene commonly referred to as the guardian of the genome and HIF1-α is a transcriptional factor that plays a key role in adaptation to hypoxia. Upon DNA damage or hypoxia, p53 or HIF1-α respectively are induced and quickly localize to the cell nucleus; whereas upon DNA repair or normoxia they must quickly concentrate in the cytoplasm for degradation. Their fast movement rate is not random and is directed by a microtubule-driven motor. Furthermore, we have shown that HIF1-α mRNA also uses the microtubule network to travel from the nucleus to the site of translation.
Drugs that bind to either tubulin or microtubules form one of the most effective classes of anticancer agents. The so-called anti-mitotic drugs usually arrest cells in mitosis leading to apoptosis. We analyzed the differential effects of taxol treatment on parental and taxol-resistant cells. Survivin is a protein that senses mitotic arrest and leading to apoptotic cell death. Despite the clinical success of microtubule-targeting agents, the emergence of acquired resistance to the drug is a limiting factor for curing cancer. Acquired drug resistance is the most common reason for the failure of drug treatment in cancer patients with initially sensitive tumors, and as such, is presently responsible for the majority of deaths from cancer. We sought to understand the timeline of events that takes place during the development of drug resistance to microtubule-targeting agents. While it has been widely published that a major mechanism of resistance to anti-mitotic drugs is due to acquired β-tubulin mutations, we have shown loss of heterozygosity of the wild type allele of β-tubulin must occur to confer higher levels of resistance. To overcome drug resistance to microtubule-targeting agents we have focused on alternate drug regimens that are active in anti-mitotic drug-resistant cells. The synergistic interaction of farnesyltransferase inhibitors (FTI) and taxol has recently been introduced in the clinic and surprisingly overcomes taxol resistance. We have shown that FTIs increase the binding of taxol to β-tubulin tubulin, even in taxol-resistant cells. In an effort to dissect the molecular mechanism underlying the synergistic interaction of FTIs with taxanes, we have recently discovered that FTIs affect microtubule acetylation and stability, partly due to inhibition of the tubulin deacetylase HDAC6. The inhibition of HDAC6 by the FTI lonafarnib leads to increased tubulin acetylation and that this is the molecular basis for the synergy of FTIs with Taxol.
La tesis titulada "Anti-microtubule drugs: Mechanisms of Action and Resistance.
Agents anti-microtubulars: Mecanismes d'Acció i Resistència" tiene cuatro objetivos principales. El primer objetivo ha sido descifrar, entender y manipular el papel del tráfico microtubular. El segundo objetivo se ha centrado en el mecanismo de acción de los agentes que tienen como diana los microtúbulos. En el tercer objetivo se ha desarrollado un modelo para explicar la quimioresistencia adquirida a estos agentes anti-microtubulares. En el cuarto y ultimo objetivo se han probado nuevos agentes anti-microtubulares que son activos en casos de quimioresistencia adquirida o endógena a agentes anti-microtubulares.
Los microtúbulos, componentes dinámicos y estructurales de las células, son esenciales para el desarrollo y mantenimiento de la forma celular, el movimiento y división celulares. Se ha intentado entender el papel que juegan los microtúbulos en el contexto celular. Los microtúbulos actúan como "autopistas activas" dentro de las células y son esenciales para la correcta operación celular ya que controlan la entrega, localización y función de una multitud de proteínas. El primer objetivo de la tesis se ha centrado en las proteínas p53 y HIF1-α. Estas dos proteínas son principales protagonistas en la progresión tumoral y la angiogenesis. La p53 es un gen supresor de tumor comúnmente llamado el guardián del genoma y el HIF1-α es un factor de trascripción que tiene un papel crucial en la adaptación celular a la hipoxia (la baja concentración de oxigeno). En los casos de el daño al ADN o hipoxia, la p53 o el HIF1-α, respectivamente, son inducidos y se translocan rápidamente al núcleo celular, mientras que cuando el ADN ha sido reparado o el regreso al estado de normoxia, las proteínas se deben concentrar en el citoplasma para su degradación por el proteosoma. El rápido movimiento de estas proteínas no es aleatorio y esta dirigido por un motor microtubular. Además, se ha demostrado que el ARN mensajero del HIF1-α también usa la red de microtúbulos para llegar del núcleo al sitio de translación a proteína.
Las drogas que se unen a la tubulina forman parte de una de las clases más efectivas de agentes anticáncer. Estas drogas comúnmente referidas como antimitóticas arrestan las células en mitosis conllevando a la apoptosis celular. Se han analizados los diferentes efectos del tratamiento del taxol en líneas celulares sensibles al taxol y en líneas celulares resistentes al taxol derivadas de las líneas sensibles. La survivina es una proteína clave en el pase del arresto mitótico en la célula a la muerte por apoptosis. A pesar del éxito clínico de las drogas antimicrotubulares, un factor que limita su aplicación universal es la apariencia de focos resistentes. La quimioresistencia adquirida es la razón más común del fracaso de la quimioterapia en pacientes con cáncer que inicialmente responden al tratamiento. En el tercer objetivo de la tesis se ha descrito un modelo temporal para explicar el desarrollo de la quimioresistencia en líneas celulares tratadas continuamente con drogas antimicrotubulares. Aunque se ha publicado extensamente que el principal mecanismo de quimioresistencia a los agentes antimicrotubulares es debido a la apariencia de mutaciones en el gen de la beta-tubulina, en este objetivo se ha demostrado que es necesario que también haya perdida de heterocigosidad en el alelo wt para que las células tengan unos altos niveles de resistencia. En el cuarto objetivo se han estudiado nuevos regimenes de quimioterapia que son activos en las células resistentes. La interacción sinergística entre los inhibidores de la farnesiltransferasa (FTI) y los taxanos se introdujo recientemente en la clínica y es muy activa contra la resistencia al taxol. Se ha demostrado que los FTIs intensifican la unión del taxol a la beta-tubulina, incluso en células resistentes al taxol. Los FTIs afectan la acetilación microtubular, a través de la inhibición de la HDAC6, la tubulina deacetilasa. La mayor acetilación de la tubulina, conlleva a una tubulina más estable y más propensa a la unión del taxol.