published_or_final_version / abstract / toc / Dentistry / Doctoral / Doctor of Philosophy

No description available.

Cardiac fibrosis is the excess deposition of myocardial extracellular matrix components, which increases tissue stiffness and heterogeneity, causing impaired diastolic/systolic function and arrhythmias, and eventually leading to heart failure and death. There are no available treatments for cardiac fibrosis. Myofibroblasts mediate fibrosis, and are characterized by hypersynthesis of collagens, decreased migration, and increased α-smooth muscle actin, which is incorporated into stress fibers, imparting contractility. Scleraxis is a transcriptional regulator of collagen-rich tissues, increased in response to the same stimuli that drive the myofibroblast phenotype, such as cyclic stretch. We show that Scleraxis mediates the conversion of cardiac fibroblasts to myofibroblasts, by increasing myofibroblast marker expression and contraction, and decreasing migration. Additionally, a proximal 1500 bp human SCLERAXIS promoter is activated by stretch and is responsive to transforming growth factor-β1. Thus, Scleraxis is a specific mechanoresponsive regulator of the myofibroblast, representing a novel target for the treatment of cardiac fibrosis.

The fibroblast growth factor family of polypeptides currently consists of nine structurally-related members. Cloning of the mouse homologue of the latest reported member of the family, FGF-9, is described in this study. Mouse Fgf9 exhibits a high level of sequence conservation with the human, rat and Xenopus counterparts. Of note is the lack of a hydrophobic signal peptide at the N-terminus of the coding sequence. The protein, however, appeared to be secreted by producer cells since a significant quantity of the protein could be purified from the culture supernatant of transfected cells. Members of the FGF family are known to bind to cell surface tyrosine kinase receptors (FGFRs) to elicit a variety of physiological responses. These receptors themselves form a family of four structurally-related tyrosine kinases and each FGF member commonly has the ability to bind several members of the FGFR family. By using in vitro plate binding assays, FGF-9 is shown in this study to bind specifically to two FGFR members: FGFR2b and FGFR3c. To further study the potential functional role of FGF-9, its expression pattern in the mouse embryo was examined by both RNase protection and RNA in situ hybridization analyses. The transcript was detected in a variety of embryonic tissues: the germinal epithelium of the central nervous system, the mesonephric cords, the somites, the gut primordia and the developing eye and ear, suggesting that the gene may have multiple roles during development. In addition, the potential involvement of FGF-9 in mediating adult brain functions was examined by double RNA in situ hybridization analysis of the distribution of both Fgf9 and Fgfr3 transcripts in the adult mouse brain. Most apparent areas of co-localization are the olfactory bulb and cerebral cortex. The two transcripts are also shown to have distinct distribution patterns in the cerebellum.

Thesis (Ph. D.) -- California Institute of Technology, 2010. / Title from home page (viewed 03/25/2010). Advisor and committee chair names found in the thesis' metadata record in the digital repository. Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2004. / Title from first page of PDF file. Document formatted into pages; contains xii, 203 p.; also includes graphics (some col.) Includes bibliographical references (p. 179-203). Available online via OhioLINK's ETD Center

Thesis (Ph. D.)--Florida State University, 2004. / Advisor: Dr. Michael Blaber, Florida State University, College of Arts and Sciences, Dept. of Chemistry and Biochemistry. Title and description from dissertation home page (viewed June 1, 2005). Document formatted into pages; contains xiii, 110 pages. Includes bibliographical references.

Hohenheim, Univ., Diss., 2007.

Mainz, Univ, Diss., 2001.

No description available.