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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.
1

Immunohistochemistry study on expression of Tumor Necrosis Factor Like Weak Inducer of Apoptosis (TWEAK) and its receptor FN14 in normal and periodontitis tissues.

Kataria, Nupur Grover January 2009 (has links)
Chapter 1: Periodontitis is a chronic inflammatory disease wherein microbial factors induce complex inflammatory and immune responses in a susceptible host. In periodontitis host-derived enzymes, cytokines and other proinflammatory mediators play an integral role in the destruction of tooth supporting structures and alveolar bone. TWEAK (TNF-like weak inducer of apoptosis), one of the members of the TNF superfamily, has recently been identified as an important inflammatory mediator. Fn14 (fibroblast growth factor-inducible 14) protein/TWEAKR has been identified as the cell surface receptor for TWEAK. TWEAK/Fn14 signaling results in multiple biologic effects including induction of inflammatory cytokines, modulating immune response angiogenesis and stimulation of apoptosis. TWEAK has also been shown to promote osteoclastic differentiation of cells from the monocyte/macrophage lineage. Expression of TWEAK and its receptor Fn14 is elevated in tissues and cells cultured from a number of chronic inflammatory diseases, such as rheumatoid arthritis, atherosclerosis, inflammatory skin, kidney and airway diseases. This review considers the biology of TWEAK and its receptor Fn14 in periodontitis. Chapter 2: Periodontitis is a chronic inflammatory disease wherein microbial factors induce complex inflammatory and immune responses in a susceptible host. In periodontitis host derived enzymes, cytokines and other proinflammatory mediators play an integral role in the destruction of tooth supporting structures and alveolar bone. TWEAK (TNF-like weak inducer of apoptosis) is one of the newest members of the TNF superfamily to be identified. Fibroblast growth factor-inducible 14 (Fn14) protein/TWEAKR has been identified as the cell surface receptor for TWEAK. TWEAK/Fn14 signaling results in multiple biologic effects including induction of inflammatory cytokines, modulating immune response angiogenesis and stimulation of apoptosis. Recently, TWEAK has also been shown to promote osteoclastic differentiation of cells from the monocyte/macrophage lineage. Expression of TWEAK and its receptor Fn14, is elevated in tissues and cells cultured from a number of chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory skin, kidney and airway diseases. Accordingly, we hypothesised that the expression of TWEAK and Fn14/TWEAKR will be increased in tissue samples from periodontitis patients. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1367201 / Thesis (D.Clin.Dent.) - University of Adelaide, School of Dentistry, 2009
2

The TWEAK-Fn14 Ligand Receptor Axis Promotes Glioblastoma Cell Invasion and Survival Via Activation of Multiple GEF-Rho GTPase Signaling Systems

Fortin Ensign, Shannon Patricia January 2013 (has links)
Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors, characterized by a highly invasive cell population. GB tumors develop treatment resistance and ultimately recur; the median survival is nearly fifteen months and importantly, the invading cell population is attributed with having a decreased sensitivity to therapeutics. Thus, there remains a necessity to identify the genetic and signaling mechanisms that promote tumor spread and therapeutic resistance in order to develop new targeted treatment strategies to combat this rapidly progressive disease. TWEAK-Fn14 ligand-receptor signaling is one mechanism in GB that promotes cell invasiveness and survival, and is dependent upon the activity of multiple Rho GTPases including Rac1. Here, we show that Cdc42 is essential in Fn14-mediated Rac1 activation. We identified two guanine nucleotide exchange factors (GEFs), Ect2 and Trio, involved in the TWEAK-induced activation of Cdc42 and Rac1, respectively, as well as in the subsequent TWEAK-Fn14 directed glioma cell migration and invasion. In addition, we characterized the role of SGEF in promoting Fn14-induced Rac1 activation. SGEF, a RhoG-specific GEF, is overexpressed in GB tumors and promotes TWEAK-Fn14-mediated glioma invasion. Moreover, we characterized the correlation between SGEF expression and TMZ resistance, and defined a role for SGEF in promoting the survival of glioma cells. SGEF mRNA and protein expression are regulated by the TWEAK-Fn14 signaling axis in an NF-kB dependent manner and inhibition of SGEF expression sensitizes glioma cells to TMZ treatment. Lastly, gene expression analysis of SGEF depleted GB cells revealed altered expression of a network of DNA repair and survival genes. Thus TWEAK-Fn14 signaling through the GEF-Rho GTPase systems which include the Ect2, Trio, and SGEF activation of Cdc42 and/or Rac1 presents a pathway of attractive drug targets in glioma therapy, and SGEF signaling represents a novel target in the setting of TMZ refractory, invasive GB cells.
3

The expression of novel, load-induced extracellular matrix modulating factors in cardiac remodeling

Mustonen, E. (Erja) 07 September 2010 (has links)
Abstract Cardiac remodeling is defined as changes in the size, shape and function of the heart, caused most commonly by hypertension-induced left ventricular (LV) hypertrophy and myocardial infarction (MI). It is characterized by changes in cellular and extracellular compartments regulated by e.g. neurohumoral and inflammatory factors. In the present study the expression of novel, load induced factors, thrombospondin (TSP)-1 and -4, matrix Gla protein (MGP), tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14, was investigated during cardiac remodeling. Their expression in the heart was characterized using experimental models of pressure overload, hypertensive hypertrophy and MI, and the effect of hypertrophic agonists and cellular stretch was studied in vitro. The effect of beta-blocker treatment on TSP expression was also examined. TSP-1 and -4 were rapidly upregulated in response to pressure overload, and the induction of TSP-4 gene expression was attenuated in hypertrophied heart. After MI, TSP-1 and -4 mRNA and TSP-1 protein levels were increased, and the induction was attenuated by metoprolol. TSP-1 and -4 expression correlated with natriuretic peptide expression and LV remodeling after MI. In hypertensive hypertrophy, only TSP-4 expression decreased after metoprolol treatment and was correlated with LV remodeling. MGP gene expression was increased in response to pressure overload and MI both in the early and late phase of cardiac remodeling. MGP protein levels were increased in the acute phase of post-MI remodeling and in hypertensive hypertrophy. In vitro, angiotensin II increased MGP gene expression in myocytes and fibroblasts, whereas expression decreased in response to mechanical stretch. In response to increased cardiac load Fn14 expression was upregulated both acutely and chronically while TWEAK expression remained relatively constant. Fn14 localized mainly to fibroblasts in the inflammatory area while TWEAK localized to myocytes and endothelial cells. In myocytes, Fn14 expression was induced by hypertrophic agonists and mechanical stretch in contrast to stabile or decreased TWEAK expression. This study provides new insights into the expression of the studied novel factors in cardiac remodeling. The distinct expression of TSPs in pressure overload and post-MI suggests that TSP-1 and -4 may have unique roles in the remodeling process. The results also imply that MGP is part of the common gene program of hypertrophic remodeling in vivo and contributes to the molecular basis of cardiac hypertrophy. Finally, the study demonstrates differential regulation of TWEAK and Fn14 expression in the heart and emphasizes the importance of Fn14 as a mediator of TWEAK/Fn14 signaling and as a potential target of therapeutic interventions.
4

Genetic and Pharmacologic Inhibition of Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein Expression Protects Against Denervation-Induced Skeletal Muscle Atrophy In Vivo

Lejmi Mrad, Rim January 2016 (has links)
Skeletal muscle atrophy is a debilitating condition caused by pathological conditions including cancer cachexia, disuse and denervation. Disuse atrophy is characterized by reduction in fiber size, fiber-type change and induction of markers of atrophy such as MuRF1 and Fn14. Recent studies have focused on understanding the fundamental role of signalling pathways and the proteolytic system in response to muscle atrophy. Unfortunately the exact mechanisms behind atrophy remain poorly understood. I recently demonstrated that cIAP1 and/or cIAP2 proteins are critical regulators of NF-kB activation, which has been shown to be involved in skeletal muscle atrophy. Here, I used genetic and pharmacological means to investigate the role of cIAP1 in a denervation-induced skeletal muscle atrophy model. Interestingly, I found that upon denervation loss of cIAP1 rescues muscle fiber size, prevents fiber-type changing and inhibits the expression of MuRF1 and Fn14. Moreover, treatment of mice with Smac mimetic compounds (SMC), a novel class of small molecule IAP antagonists, showed successful knockdown of cIAP1 in muscle and protects against denervation-induced muscle atrophy. Taken together, these data reveal that cIAP1 is both a novel mediator of skeletal muscle atrophy and an important therapeutic target.

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