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Thesis (Ph.D.)--Tufts University, 2004. / Adviser: David E. Cochrane. Submitted to the Dept. of Biology. Includes bibliographical references (leaves 137-165). Access restricted to members of the Tufts University community. Also available via the World Wide Web;

Thesis (Ph. D.)--Florida State University, 2003. / Advisor: Dr. Michael Blaber, Florida State University, College of Arts and Sciences, Department of Chemistry and Biochemistry. Title and description from dissertation home page (viewed Aug. 24, 2004). Includes bibliographical references.

Marburg, Universiẗat, Diss. : 1993.

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Fibrotic diseases are a leading cause of morbidity and mortality in the developed world. Despite this, the lack of therapies for fibrotic pathological disease states is severe. A large part of the reason for this lack of viable therapies is due to an incomplete understanding of the early processes driving tissue fibrosis, as well as the dismal results of pharmacologic monotherapies at the clinical trial stage in humans thus far. Therefore, better understanding of the upstream mechanisms driving tissue fibrosis is imperative. One of the common mechanisms underlying all fibroses is the presence and activity of the myofibroblast, a contractile mesenchymal cell that deposits high levels of extracellular matrix. Overpersistence of myofibroblasts in the wound site lead to deposition of an acellular, nonfunctional, mechanically aberrant scar that can result in loss of tissue function and, in severe cases, eventual organ failure. Here we investigate the mechanisms under which fibroblast growth factor 2 (FGF2), one member of the mammalian fibroblast growth factor family, antagonizes activation of fibroblasts to myofibroblasts. We identify a gene and protein expression signature induced by FGF2 that is antagonistic to activated myofibroblasts, and we demonstrate that induction of this antifibrotic gene expression paradigm is antagonized by inhibition of the mitogen-activated protein kinase pathways ERK and JNK, each of which lies canonically downstream of FGF2/FGFR signaling, suggesting that the antifibrotic effects of FGF2 as an antagonist to fibroblast activation are likely dependent at least in part upon activation of these cellular signaling pathways. We further demonstrated that, independent of exogenous FGF2 stimulation, inhibition of ERK or JNK signaling in proliferating human dermal fibroblasts was sufficient to induce fibroblast activation, accompanied by a pro-fibrotic extracellular matrix gene expression paradigm. Inhibition of these pathways also resulted in distinct changes in transforming growth factor beta (TGF-β) gene expression paradigms, modulating the expression of both ligands and receptors involved in this pathway, and we verified that activation of fibroblasts via MAPK inhibition was dependent at least in part on activation of TGF-βR signaling. In contrast, inhibition of p38 MAPK was sufficient to antagonize fibroblast activation and subsequent fibrosis-associated extracellular matrix deposition, both in the presence and absence of exogenous TGF-β, via changes in gene expression antagonistic to pro-fibrotic TGF-β/TGF-βR signaling. Broadly, these data suggest that activation of ERK and JNK pathways broadly antagonize fibroblast activation and fibrosis, while activation of p38 drives fibroblast activation and pro-fibrotic fibroblast phenotypes. It is our hope that this information will lead to a better understanding of the way that cellular signaling pathways interact in order to drive fibroblast activation, and better inform the potential effects of kinase inhibitors or related therapeutics for use as anti-fibrotic therapies.

The study of mechanobiology and the cellular response to the mechanical environment plays a vital role in the understanding of the atherogenesis and the treatment of the disease state through interventions such as stent placement. Cell migration in response to complex stresses also plays a critical role in wound healing. Modeling the mechanical environment as a circular membrane with a center defect can be an accurate representation of in vivo stress gradients. In this study, we created a novel cell stretching device that exposed cells to both static and 1 Hz dynamic stretch. Using NIH 3T3 fibroblasts stained with DiI membrane stain, we were able to expose cells to the two stretch regimes for 48 hours and observe the cellular response via live cell imaging. Cells were observed at 0, 12, 24, and 48 hour time points, and analysis of the change in their radial position was used to determine if cell migration occurred. Cell displacement was calculated using both the kinematic equation and the NeoHookean constitutive model. Uncertainty of the cell displacement calculation was used in determining whether or not there was cell migration. In this study, we were able to prescribe successfully the stretch regimes and observe the cellular response to stretch. Within the bounds of our uncertainty based on the error in the hole radius estimation and our measurement of cell and membrane displacement, however, we cannot say conclusively that cell migration occurred. This study established the methods and protocols necessary for further investigation into mechanobiology, in particular, the cell response to stress environments that more closely resemble the in vivo conditions.