No description available.

Thesis (Ph. D.)--University of Virginia, 2000. / Includes bibliographical references (leaves 143-182). Also available online through Digital Dissertations.

Breast cancer is the second leading cause of cancer-related death in women worldwide. Despite more frequent and efficient screening measures, subtype-specific treatments, and overall improved patient outcomes, metastasis remains difficult to treat and accounts for 90% of breast cancer patient deaths. While the role of intercellular communication in metastasis, either among cancer cells, or between cancer cells and the tumor microenvironment is well established, additional research on specific molecular and cellular mechanisms underlying these interactions is necessary to develop novel therapeutic strategies. One mechanism that facilitates metastasis is epithelial-mesenchymal transition (EMT), which can be induced in cancer cells following the secretion of growth factors by tumor-associated macrophages (TAMs). During EMT, epithelial cells lose their cell-cell junctions, resulting in an alteration of intercellular communication. One of the junctions lost during EMT is gap junctions composed of connexin43 (Cx43), however, this is paired with an increase in expression of cytoplasmic Cx43 which binds microtubules. To elucidate the role of cytoplasmic Cx43 during EMT and breast cancer metastasis, we utilize a Cx43 mutant that has reduced binding with microtubules. We demonstrate disruption of the interaction between Cx43 and microtubules decreases mesenchymal marker expression and cell migration in vitro during EMT, and reduces breast cancer metastasis to the lungs in vivo, identifying a novel non-junctional tumorigenic role for Cx43 in metastasis and a potential therapeutic target in the treatment of breast cancer. / Doctor of Philosophy / Cancer, which is caused by the uncontrolled growth of abnormal cells, remains one of the top causes for death worldwide. Breast cancer, in particular, is the second leading cause of cancer deaths in women in the United States. With advances in screening and improved/subtype specific treatments, patient outcomes have significantly improved for localized tumors. However, the spread of cancer from the primary tumor to a distal part of the body, called metastasis, remains difficult to treat and accounts for approximately 90% of cancer-related deaths. One mechanism known to facilitate metastasis is a cellular process called epithelial-mesenchymal transition (EMT). During EMT, epithelial cells lose their cell-cell junctions and apical-basal polarity, and gain mesenchymal characteristics, becoming more motile and invasive. These characteristics facilitate the invasion of cancer cells into tissue surrounding the primary tumor as well as entry into the bloodstream and exit at a distal site, subsequently forming a secondary tumor (metastasis). In tumors, EMT is often induced through communication between cancer cells and cancer-promoting immune cells such as tumor-associated macrophages. One of the cell-cell junctions lost during EMT are connexin43 gap junctions, which are channels that facilitate the transfer of small molecules between cells, promoting communication. We utilize mammalian cell lines and a mouse breast cancer model to investigate the role of connexin43 in EMT and breast cancer metastasis. This work provides information that can be used to develop new therapeutics and strategies for the treatment or prevention of breast cancer metastasis.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

No description available.

Thesis (Ph. D.)--University of Virginia, 2006. / Includes bibliographical references. Also available online through Digital Dissertations.

Cell-cell communication between bacteria, belonging to the same species or to different species (Intra-kingdom signaling), or communication between bacteria and their animal host (Inter-kingdom signaling) is mediated through different chemical signals that are synthesized and secreted by bacteria or the host and is crucial for the survival of bacteria inside their host. The overall goal of this work was to understand the role of inter- and intra-kingdom signaling in phenotypes such as chemotaxis, colonization and biofilm formation, and virulence that are associated with infections caused by the human gastrointestinal (GI) tract pathogens. A part of our work also aimed at developing microfluidics-based models to study inter- and intra-kingdom signaling in biofilm formation, inhibition, and dispersal. We showed that norepinephrine (NE), an important host signal produced during stress, increases human opportunistic pathogen Pseudomonas aeruginosa growth, motility, attachment, and virulence, and also showed that the actions of NE are mediated primarily through the LasR, and not the RhlR QS system. We investigated the molecular mechanism underlying the chemo-sensing of the intra-kingdom signal autoinducer-2 (AI-2) by pathogens Escherichia coli and Salmonella typhimurium by performing different chemotaxis assays (capillary, microPlug and microFlow assays), and discovered that AI-2 is a potent attractant for E. coli and S. typhimurium, and that the Tsr chemoreceptor and periplasmic AI-2 binding protein LsrB are necessary for sensing AI-2, although uptake of AI-2 into the cytoplasm is not required. We concluded that LsrB, when bound to AI-2, interacts directly with the periplasmic domain of Tsr primarily at the Thr-61 and Asp-63 residues of LsrB, making LsrB the first known periplasmic-protein partner for Tsr. We fabricated a simple user-friendly microfluidic flow cell (microBF) device that can precisely measure the effect of a wide range of concentrations of single or combinations of two or more soluble signals on bacterial biofilm formation and development. We also constructed a synthetic biofilm circuit that utilizes the Hha and BdcA dispersal proteins of E. coli along with a quorum sensing (QS) switch that works based on the accumulation of the signal N-(3-oxo-dodecanoyl)-L-homoserine lactone (3-o-C12HSL) and implemented it in an upgraded �BF device. We showed that a QS system may be utilized with biofilm dispersal proteins to control consortial biofilm formation by removing an existing biofilm and then removing the biofilm that displaced the first one. These types of synthetic QS circuits may be used to pattern biofilms by facilitating the re-use of platforms and to create sophisticated reactor systems that will be used to form bio-refineries.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Virginia, 2000. / Spine title: Palladin & actin organization. Includes bibliographical references (leaves 209-251). Also available online through Digital Dissertations.

Thesis (Ph. D.)--University of Virginia, 1999. / Spine title: Sphingolipid signaling in platelets. Includes bibliographical references (p. 134-144). Also available online through Digital Dissertations.