Browsing by Subject "Collagen"
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Item Dynamic Changes in Collagen Organization Modulate Cervical Remodeling During Pregnancy and Parturtion: New Insights and the Potential for Improved Clinical Tools to Combat Preterm Birth(2012-07-17) Akins, Meredith Lynne; Mahendroo, MalaPreterm birth affects approximately 500,000 infants in the Unites States alone and is the second highest cause of infant morbidity in this country. Obstetricians still do not have reliable tools to diagnose or treat women presenting with premature labor. Understanding mechanisms by which the cervix remodels during term and preterm pregnancy is critical to formulate better methods for detection and treatment of preterm birth. The focus of this study was to identify how cervical collagen is reorganized throughout pregnancy to allow the cervix to become compliant for parturition. Beginning early in pregnancy a reduction in cervical collagen cross-links as well as a decline in matricellular proteins contribute to the changing cervical extracellular matrix environment. These cumulative changes result in increased collagen fibril diameter, as well as a progressive increase in tissue distensibility and a decline in tissue stiffness. Changes in collagen morphology over pregnancy can be visualized via non-invasive second harmonic generation (SHG). Quantification of specific morphological features such as collagen fiber diameter or porosity reveal progressive changes that allow one to distinguish stages in pregnancy. In addition, analysis of SHG images from two preterm birth models as well as one postterm pregnancy model validate the ability to use quantitative morphological measurements to distinguish normal from abnormal cervical remodeling. These findings suggest SHG technology is a powerful tool that may have potential clinically to predict preterm birth. In closing these studies have identified early and progressive changes in processing and assembly of collagen fibrils as well as changes in other ECM components that likely contribute to the incremental change in cervical tensile strength required for birth.Item Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-Mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma(2015-07-24) Aguilera, Kristina Yolanda; Pearson, Gray W.; Brekken, Rolf A.; Minna, John D.; Terada, LanceAn extracellular matrix (ECM) rich in fibrillar collagens is a principal component of pancreatic ductal adenocarcinoma (PDA). The ECM provides structural support for the tumor and facilitates tumor cell survival and chemoresistance by activating cell surface receptors on tumor cells. Fibrillar collagens bind the collagen-specific receptor tyrosine kinase discoidin domain receptor 1 (DDR1), implicated in regulating cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. Additionally, collagen has been shown to promote chemoresistance in pancreatic tumor cells. I hypothesize that the regulation of collagen-mediated DDR1 signaling promotes chemoresistance. Collagen expression and deposition is a complex process that is orchestrated in part by the matricellular protein SPARC. SPARC expression in human PDA patients correlates with improved chemoresponse; however, the mechanism underlying this is unclear. I proposed that SPARC reduces collagen binding to collagen receptors. Structural studies identified that SPARC and DDR1 share the same collagen-binding site. I demonstrated that SPARC inhibited collagen binding to DDR1 via in vitro binding assays and cell-based activity assays. To determine the functional relevance of Sparc expression and collagen-mediated Ddr1 activation in PDA, Sparc-null (Sparc-/-) mice were crossed with a GEMM of PDA, KIC (LSL KrasG12D/+; Ink4aArflox/lox; p48Cre/+). Survival was reduced and tumors were more aggressive in Sparc-/-; KIC mice. Tumors from these animals also displayed elevated Ddr1-mediated signaling. Human PDA, and primary PDA cell lines isolated from Sparc+/+; KIC and Sparc-/-; KIC animals, were used to probe collagen signaling and collagen activation of DDR1 stimulated downstream intermediates including protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1). Furthermore, utilization of a novel DDR1 small molecule inhibitor (7rh) abrogated collagen-induced DDR1 signaling and blunted tumor cell colony formation, migration, and enhanced sensitivity to gemcitabine. Additionally, 7rh inhibited Ddr1 signaling in syngeneic, genetic, and human xenograft pancreatic tumors and was well tolerated. Therapy studies combining standard chemotherapy (gemcitabine plus nab-paclitaxel) with 7rh in vivo dramatically improved survival of mice compared to standard therapy alone. These data confirm that inhibition of collagen signaling in PDA is an attractive therapeutic strategy and demonstrate that DDR1 is a target that can be inhibited pharmacologically.Item [UT Southwestern Medical Center News](2009-03-17) Stafford, Erin Prather