The endoplasmic reticulum (ER) is a cellular organelle responsible for lipid biosynthesis, protein folding, drug detoxification and regulation of cellular calcium levels. One third of all cellular proteins are folded and assembled in the ER, including most membrane-bound and secreted proteins that are responsible for inter-cellular signaling. As such, the ER has evolved a series of pathways collectively called Endoplasmic Reticulum Quality Control (ERQC) that ensure proteins that are properly folded, as errantly folded proteins can be toxic to the cell. These pathways play a diverse role in many human diseases. In neurodegenerative diseases such as Huntington's disease, the accumulation of protein plaques can be prevented by over-expression of protein chaperones, suggesting that weakened folding machinery causes the disease phenotype. In the case of diseases such as Cystic Fibrosis that are caused by genetic mutation to cell surface proteins, ERQC machinery degrades these mutated proteins despite their ability to function properly if they were allowed to exit the ER. In cancer, the ability of ERQC machinery to protect cells from stress enables tumor cells to survive and thrive in hypoxic and nutrient-poor environments. Systems biology methods have enabled the study of signaling pathways in human disease across the cell. However, with this breadth comes a limited ability to focus on particular areas of interest such as the ER. To address this, this thesis applies systems biology methods specifically to ER and ERQC pathways to better understand their role in human disease. We first characterize the proteins that reside in the ER and Golgi through comprehensive analysis of peptides identified in ER and Golgi fractions via mass spectrometry, providing the first experimentally-derived ER proteome. We then use this list of ER proteins to identify ER signaling pathways that distinguish between breast cancer subtypes to provide novel therapeutic approaches to treating / Le réticulum endoplasmique (RE) est un organelle cellulaire responsable de la biosynth`ese des lipides, du repliement des protéines, de la désintoxication et de la régulation des niveaux cellulaires de calcium. Un tiers des protéines cellulaires est plié et assemblé dans le RE, y compris la plupart des protéines liées à la membrane et des protéines sécrétées responsables de la signalisation inter-cellulaire. Ainsi, le RE a mis au point une série de voies de signalisation collectivement appelées Contrôle de Qualité du Réticulum Endoplasmique (CQRE) qui assurent que les protéines soient correctement pliées, étant donné que les protéines incorrectement pliées peuvent être toxiques pour la cellule. Ces voies jouent divers rôles dans de nombreuses maladies humaines. Dans les maladies neurod égénératives telles que la maladie de Huntington, l'accumulation de plaques de protéines peut être évitée par la sur-expression de protéines chaperons, ce qui sugg`ere qu'un affaiblissement de la machinerie de pliage cause le phénotype de cette maladie. Dans le cas de maladies comme la Fibrose Cystique qui sont causées par une mutation génétique des protéines de la membrane cellulaire, le CQRE dégrade ces protéines mutées bien que celles-ci fonctionneraient correctement si elles avaient été autorisées à quitter le RE. Dans le cancer, la capacité du CQRE à protéger les cellules contre le stress permet aux cellules tumorales de survivre et de se développer dans des environnements hypoxiques et pauvres en éléments nutritifs. Les méthodes de biologie des syst`emes ont permis l'étude des voies de signalisation dans les maladies humaines à travers la cellule. Cependant, avec cette large étendue, il devient difficile de se concentrer sur certains domaines d'intérêt tels que le RE. Pour résoudre ce problme, cette thse applique les méthodes de la biologie des syst`emes spécifiquement au RE et aux voies de signalisation du CQRE po

Doctor of Philosophy(PhD) / In this thesis, we consider Markov models for matched sequences. De¯ne fij(t) = P(X(t) = i; Y (t) = jjX(0) = Y (0)); where fij is the joint probability that, for a given site, the ¯rst and second sequences have the values i and j at a given site, given that they were the same at time 0. This can generalized to several sequences. The sequences (taxa) are then arranged in an evolutionary tree (phylogenetic tree) depicting how taxa diverge from their common ancestors. We develop tests and estimation methods for the parameters of di®erent models. Standard phylogenetic methods assume stationarity, homogeneity and reversibility for the Markov processes, and often impose further restrictions on the parameters. The parameters in these cases are estimated using many popular packages, including PHYLIP and PAUP*. We describe a new and more general method for calculating the joint probability distribution under stationary and homogeneous models for the more general models with some weakening of the stationarity and homogeneity assumptions. We describe the method for a two edged tree and then extend it to the case for a K tipped tree. We discuss the case of a ¯ve edged tree for a set of bacterial sequences for which stationarity and homogeneity are not present. This data set is very similar to that of Galtier and Gouy (1995), and the search for methods appropriate for its analysis has provided the raison d'etre for this work. The extension we propose is to allow non-stationarity, so that from the root of the tree we permit di®erent Markov processes to operate along different descendant lineages; furthermore, we permit non-homogeneous Markov processes to operate across the tree. We obtain methods that

Thesis (M.S.)--University of Missouri--Rolla, 2007. / Vita. The entire thesis text is included in file. Title from title screen of thesis/dissertation PDF file (viewed February 6, 2008) Includes bibliographical references (p. 36).

Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2006. / Source: Dissertation Abstracts International, Volume: 68-02, Section: B, page: 0696. Adviser: Nikolaos V. Sahinidis. Includes bibliographical references (leaves 138-149) Available on microfilm from Pro Quest Information and Learning.

Thesis (M.S.) OGI School of Science & Engineering at OHSU, November 2007. / Includes bibliographical references (leaves 41 - 45).

Thesis (M.S.)--Georgia State University, 2007. / Title from file title page. Yanqing Zhang, committee chair; Saeid Belkasim, Yingshu Li, committee members. Electronic text (79 p. : ill. (some col.)) : digital, PDF file. Description based on contents viewed Nov. 5, 2007. Includes bibliographical references (p. 76-78).

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of California, San Francisco, 2006. / Source: Dissertation Abstracts International, Volume: 68-01, Section: B, page: 0026. Adviser: Jack Taunton.

Thesis (Ph. D.)--University of California, San Francisco, 2006. / Source: Dissertation Abstracts International, Volume: 68-01, Section: B, page: 0026. Adviser: Jack Taunton.

Thesis (Ph.D.)--University of California, Berkeley, 2006. / (UMI)AAI3253939. Source: Dissertation Abstracts International, Volume: 68-02, Section: B, page: 0697. Adviser: Glenys Thomson.