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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
101

Experimental and Computational Analysis of Polyglutamine-Mediated Cytotoxicity

Tang, Matthew 05 March 2012 (has links)
Expanded polyglutamine proteins are known to be the causative agents of a number of human neurodegenerative diseases but the molecular basis of their cytoxicity is still poorly understood. Polyglutamine tracts may impede the activity of the proteasome, and evidence from single cell imaging suggests that the sequestration of polyglutamine proteins into inclusion bodies can reduce the proteasomal burden and promote cell survival, at least in the short term. The presence of misfolded protein also leads to activation of stress kinases such as p38MAPK, which can be cytotoxic. The relationships of these systems are not well understood. We have used fluorescent reporter systems imaged in living cells, and stochastic computer modeling to explore the relationships of expanded polyglutamine proteins, p38MAPK activation, generation of reactive oxygen species (ROS), proteasome inhibition, and inclusion body formation. In cells expressing a polyglutamine protein, inclusion body formation was preceded by proteasome inhibition but cytotoxicity was greatly reduced by administration of a p38MAPK inhibitor. Computer simulations suggested that without the generation of ROS, the proteasome inhibition and activation of p38MAPK would have significantly reduced toxicity. Our data suggest a vicious cycle of stress kinase activation and proteasome inhibition that is ultimately lethal to cells. There was close agreement between experimental data and the predictions of a stochastic computer model, supporting a central role for proteasome inhibition and p38MAPK activation in inclusion body formation and ROS-mediated cell death.
102

Evolutionarily Conserved Function of Huntingtin in Cellular Dynamics Related to Cell Adhesion and the Cytoskeleton

Thompson, Morgan Nicole 15 March 2013 (has links)
Huntington's disease (HD) is a rare, dominantly inherited neurodegenerative disorder characterized by progressive chorea, emotional and behavioral disturbances, and cognitive decline. The single, causative mutation is an expanded trinucleotide repeat of cytosine, adenosine, and guanine (CAG) of more than 37 residues in the HD gene (currently referred to as HTT). Genetic evidence suggests that the CAG repeat expansion results in a gain of huntingtin function. While huntingtin and its numerous interactors have been implicated in a variety of essential cellular processes, the role of the full-length, endogenous protein remains unclear. Multiple studies have implicated huntingtin in processes related to cytoskeletal structure and dynamics in HD patients and model organisms. However, alterations in cellular dynamics related to the cytoskeleton — including cell adhesion — have not been characterized in a comprehensive, rigorous manner. Using Mus musculus genetic models of the HD mutation and/or deficiency and a Dictyostelium discoideum genetic deficiency model, I have undertaken an investigation of evolutionarily conserved huntingtin function in the cytoskeleton and cell adhesion. The results of these studies support a role for huntingtin in cell-cell and cell-substrate adhesion, as well as maintaining actin cytoskeletal structure. Furthermore, my thesis research sets the stage for future work to elucidate the molecular mechanism by which huntingtin is acting and determine the effect of the CAG repeat expansion on huntingtin function. Evolutionary conservation affords an invaluable tool to identify crucial function(s) of the huntingtin molecule and the effect of the pathogenic HD mutation on function, enabling therapeutic development while providing novel insights into cytoskeletal biology and cell adhesion.
103

Overexpressing Fragments of CREB-Binding Protein (CBP) to Block Transcriptional Dysregulation and Toxicity in Huntington's Disease

Hosier, Gregory 19 July 2012 (has links)
Huntington’s disease (HD) is caused by expression of the huntingtin gene containing an expanded CAG repeat. N-terminal mutant huntingtin protein (N-mHtt) accumulates in the nucleus and impairs transcription of a subset of genes through incorporation into transcriptional complexes or sequestration of proteins away from the promoter. CREB-binding protein (CBP) is a transcriptional co-activator and acetyltransferase (AT) that binds to N-mHtt. We hypothesized that overexpressing CBP fragments that lack a promoter association domain would block N-mHtt-mediated transcriptional dysregulation and toxicity. We found that overexpressing full-length CBP or CBP fragments did not reverse transcriptional dysregulation, but did decrease toxicity in a cell model of HD. Overexpressing fragments of CBP containing the AT domain increased toxicity in wild-type cells, while overexpressing a fragment lacking this domain had no effect. We conclude that excess AT activity was detrimental in wild-type cells, while overexpressing CBP or CBP fragments was protective in HD cells.
104

Development and degeneration of the sensory control of reach-to-eat behaviour

Sacrey, Lori-Ann Rosalind January 2012 (has links)
The reach-to-eat movement, in which a hand is advanced towards a food item, shapes to grasp the food item, and withdrawals to place the food item into the mouth for eating, is a behaviour that is performed daily. The movement is controlled by two sensory systems, vision to guide hand advance and grasping, and somatosensation to guide hand withdrawal and mouth placement. The purpose of the present thesis was to examine how the sensory control of reaching-to-eat develops in infancy and degenerates following neurodegenerative disorder. The tight coupling of vision to hand advance and somatosensation to hand withdrawal has a developmental profile from six months to one year of age. That is, six-month-old infants rely on vision to advance their hand, grasp the target, and withdrawal the target to the mouth. By twelve months of age, infants display the adult pattern of coupling vision to hand advance and grasping. The tight coupling of vision to hand advance degenerates with basal ganglia disease, such that subjects with Parkinson’s disease and Huntington’s disease show an overreliance on vision to guide hand advance for grasping and hand withdrawal for mouth placement. The results of the thesis demonstrate that efficient use of sensory control to guide motor behaviour is an important aspect of development that is disrupted by neurodegenerative disease. / xiv, 286 leaves : ill. ; 29 cm
105

Att leva med Huntingtons sjukdom : Ur ett personperspektiv / To live with Huntington's disease : From individuals perspectives

Larsson, Matilda, Laiback, Emma January 2014 (has links)
Huntingtons sjukdom är en ärftlig degenerativ sjukdom som förekommer hos 800-1000 personer i Sverige. Tidigare forskning visar på bristfällig kunskap om sjukdomen hos vårdpersonal vilket innebär ett stort lidande för de drabbade. För att skapa en djupare kunskap krävs att vårdpersonal lyssnar till personers upplevelser. Syftet med studien var att belysa personers upplevelse av att leva med Huntingtons sjukdom. För att få en överblick av forskningsläget genomfördes en systematisk sökordsbaserad litteraturstudie. Totalt elva artiklar granskades och kodades. Resultatet presenteras i tre huvudrubriker: upplevelser i relation till sjukdomen, upplevelser i relation till vården och upplevelser i relation till livet. Resultatet visade att lidande var centralt i samtliga upplevelser. Resultatet diskuteras mot bakgrund av Katie Erikssons lidandeteori. Avslutningsvis belyses betydelsen av fördjupad kunskap från vårdpersonal för att minska vårdlidandet och därmed minska livslidandet. Ytterligare forskning inom ämnet krävs för att vårdpersonal ska kunna bemöta personer med Huntingtons sjukdom på bästa möjliga sätt. / Huntington’s disease (HD) is a genetic degenerative disease affecting 800-1000 persons in Sweden. Previous research indicate that lack of knowledge about the disease among health care professionals adds to the suffering of persons with HD. Knowledge about the experiences of people living with the disease is required to improve the care. The aim of this study was to examine peoples´ experiences of living with Huntington’s disease. In order to get insights on the actual situation a systematic literature review was conducted. A total sample of eleven articles was reviewed and coded, resulting in three main themes: Experiences regarding the disease, Experiences regarding care and Experiences regarding life. The result showed that suffering was key to understanding the experience of living with the disease. The result of this study is discussed with reference to Katie Eriksson’s theory of suffering. Further research is required in order to improve the care for people with HD. By listening to the experiences of people affected by HD, health care professionals can learn how to create the best encounter possible and thus relieve some aspects of suffering.
106

Experimental and Computational Analysis of Polyglutamine-Mediated Cytotoxicity

Tang, Matthew 05 March 2012 (has links)
Expanded polyglutamine proteins are known to be the causative agents of a number of human neurodegenerative diseases but the molecular basis of their cytoxicity is still poorly understood. Polyglutamine tracts may impede the activity of the proteasome, and evidence from single cell imaging suggests that the sequestration of polyglutamine proteins into inclusion bodies can reduce the proteasomal burden and promote cell survival, at least in the short term. The presence of misfolded protein also leads to activation of stress kinases such as p38MAPK, which can be cytotoxic. The relationships of these systems are not well understood. We have used fluorescent reporter systems imaged in living cells, and stochastic computer modeling to explore the relationships of expanded polyglutamine proteins, p38MAPK activation, generation of reactive oxygen species (ROS), proteasome inhibition, and inclusion body formation. In cells expressing a polyglutamine protein, inclusion body formation was preceded by proteasome inhibition but cytotoxicity was greatly reduced by administration of a p38MAPK inhibitor. Computer simulations suggested that without the generation of ROS, the proteasome inhibition and activation of p38MAPK would have significantly reduced toxicity. Our data suggest a vicious cycle of stress kinase activation and proteasome inhibition that is ultimately lethal to cells. There was close agreement between experimental data and the predictions of a stochastic computer model, supporting a central role for proteasome inhibition and p38MAPK activation in inclusion body formation and ROS-mediated cell death.
107

An investigation of visuospatial orientation and mental rotation in patients with Alzheimer's disease and patients with Huntington's disease /

Lineweaver, Tara T. January 1999 (has links)
Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 1999. / Vita. Includes bibliographical references (leaves 105-113).
108

Bimanual coordination in Huntington's disease and Parkinson's disease.

Gonsalves, Crystal, Unknown Date (has links)
Thesis (M.Sc.)--University of Ottawa, 2008. / Includes bibliographies.
109

Bimanual coordination in Huntington's disease and Parkinson's disease

Gonsalves, Crystal, Unknown Date (has links)
Thesis (M.Sc.)--University of Ottawa, 2008. / Includes bibliographies.
110

The normal function of the huntingtin protein : a structure/function analysis /

Clabough, Erin Beth Doudera. January 2006 (has links)
Thesis (Ph. D.)--University of Virginia, 2006. / Includes bibliographical references (leaves 181-233). Also available online through Digital Dissertations.

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