<p>Heparan sulfate (HS) is an unbranched and negatively charged polysaccharide of the glycosaminoglycan family, based on the repeated (GlcNAcα1-4GlcAβ1-4)disaccharide structure. The HS backbone is modified by epimerization and sulfation in various positions. HS chains are composed of <i>N</i>-sulfated (NS) domains – predominant locations for further modification steps –, the poorly modified <i>N</i>-acetylated (NA) domains and the alternating NA/NS-domains. HS is present at the cell surface and in the extra-cellular matrix and interacts at these sites with various proteins involved in numerous biological processes, such as angiogenesis. Both pro- and anti-angiogenic proteins can interact with HS and this study was focused on how HS binds to the anti-angiogenic proteins endostatin (ES) and histidine-rich glycoprotein (HRGP) and to pro-angiogenic fibroblast growth factors (FGFs).</p><p>Here we show that ES recognizes NS-domains in HS spaced by NA-disaccharides, and that binding to ES is abolish through cleavage at these NA-disaccharides. HRGP335, a peptide derived from the His/Pro-rich domain of HRGP is shown to bind to heparin and HS to the same extent as full-size HRGP, in a Zn²⁺-dependent manner. Moreover, the ability of HRGP to inhibit endothelial cell migration is located to the same region of the protein. We analyzed HS structure in respect to binding to HRGP335 and FGF-2, and show that the ability of HS to bind to those proteins depends on chain length and composition. Finally, the role of HS in FGF–HS–FGF receptor ternary complexes is evaluated using biosynthetic analogs of NS-domains. For stabilization of such complexes the overall sulfation degree of HS seems to play a more pronounced role than the exact distribution of sulfate groups.</p><p>The results presented in this thesis contribute to a greater understanding of the role of HS in angiogenesis and may provide valuable information for the development of cures against angiogenesis-related disorders.</p>

Heparan sulfate (HS) is an unbranched and negatively charged polysaccharide of the glycosaminoglycan family, based on the repeated (GlcNAcα1-4GlcAβ1-4) disaccharide structure. The HS backbone is modified by epimerization and sulfation in various positions. HS chains are composed of N-sulfated (NS) domains – predominant locations for further modification steps –, the poorly modified N-acetylated (NA) domains and the alternating NA/NS-domains. HS is present at the cell surface and in the extra-cellular matrix and interacts at these sites with various proteins involved in numerous biological processes, such as angiogenesis. Both pro- and anti-angiogenic proteins can interact with HS and this study was focused on how HS binds to the anti-angiogenic proteins endostatin (ES) and histidine-rich glycoprotein (HRGP) and to pro-angiogenic fibroblast growth factors (FGFs). Here we show that ES recognizes NS-domains in HS spaced by NA-disaccharides, and that binding to ES is abolish through cleavage at these NA-disaccharides. HRGP335, a peptide derived from the His/Pro-rich domain of HRGP is shown to bind to heparin and HS to the same extent as full-size HRGP, in a Zn2+-dependent manner. Moreover, the ability of HRGP to inhibit endothelial cell migration is located to the same region of the protein. We analyzed HS structure in respect to binding to HRGP335 and FGF-2, and show that the ability of HS to bind to those proteins depends on chain length and composition. Finally, the role of HS in FGF–HS–FGF receptor ternary complexes is evaluated using biosynthetic analogs of NS-domains. For stabilization of such complexes the overall sulfation degree of HS seems to play a more pronounced role than the exact distribution of sulfate groups. The results presented in this thesis contribute to a greater understanding of the role of HS in angiogenesis and may provide valuable information for the development of cures against angiogenesis-related disorders.

Augmented Soft Tissue Mobilization, a massage therapy which uses a solid instrument rather than human fingers to treat musculoskeletal injuries, has been successful in treating tendinitis. Davidson et al. studied the functional and morphological affects of ASTM on collagenase induced Achilles tendinitis in Sprague-Dawley rats. Morphological observations showed a significant increase in the number and activation of fibroblasts in the ASTM treated Groups. The authors suggested that the physical force of ASTM may promote tendon healing via increased fibroblast recruitment. An important, but unexplained, question is how ASTM would affect the fibroblasts of native, noncollagenase injured, tendons. Studies have shown that mechanical forces can alter cellular functions. The purpose of this study was to examine the morphological changes in native Sprague-Dawley rat Achilles tendons after ASTM therapy using different application pressures.Three animal Groups were randomly established: A) control Group with no ASTM; B) light ASTM with 1 Newton of pressure; and C) heavy ASTM with 3 Newtons of pressure. Upon completion of the therapy, the Achilles tendons of each Group were examined with light and electron microscopy techniques to assess fibroblast number, tendon morphology, and the presence of type I and type III collagen. Fibroblast counts from each Group were compared using a two-way ANOVA, multiple regression, and curvilinear regression analysis. Morphological differences were shown between the three Groups, especially between the non force Group and the two force Groups. The ASTM Group treated with one Newton demonstrated the greatest mean fibroblast count (165.1+/-55.8&160.7+/-49.8). Electron microscopy revealed the presence of activated fibroblasts in the tendons of the two force Groups, ASTM Groups. Polarizing microscopy showed a dramatic increase in the amount of Type III collagen in the two force Groups compared to the non force Group.Ball State UniversityMuncie, IN 47306

Basic fibroblast growth factor (FGF-2) is a trophic molecule involved in a number of functions within the central nervous system (CNS), including a prominent role in the regulation of CNS responses to injury. Prior studies suggest that rats recover differently from injury inflicted to different regions and at different ages throughout development, and that FGF-2 might underlie this phenomenon. This thesis examined whether the functional and structural outcome following bilateral injury to the motor cortex inflicted at postnatal day (P10) could be ameliorated by exogenous administration of a growth factor (FGF-2). Four complimentary studies were conducted that each assessed the role of FGF-2 in mediating recovery from bilateral motor cortex injury inflicted at P10. We found that FGF-2 improves physiological, anatomical, and functional outcome from bilateral lesions to motor cortex at P10. / xiii, 171 p. : ill. ; 28 cm.

Basic fibroblast growth factor (bFGF) has been implicated in the brain's trophic response to injury. This thesis examined the effects of endogenous bFGF on brain plasticity and recovery of behavioral function following cortical injury in adult rats. The first experiment investigated the post-lesion time course of the astrocytic expression of bFGF. Subsequent experiments examined the effects of injury-induced bFGF on neuroonal morphology, cortical morphology, and post-lesion behavioral deficits. Following motor cortex injury, endogenous bFGF prevented neuritic degeneration in layer V pyramidal neurons in Zilles' area Fr2 and promoted recovery of function in the Whishaw Reaching Task. Housing rats in an enriched environment prior to cortical injury enhanced the expression of bFGF but did not increase cortical thickness nor reduce post-lesion behavioral deficits (relative to laboratroy-housed rats). Collectively, these experiments indicate that injury-induced bFGF plays a role in potentiating recovery from brain damage. This implies that bFGF may be beneficial as a treatment following brain injury. / x, 123 p. ; 28 cm.

This thesis examined the role of exogenous basic fibroblast growth factor (FGF-2) in stimulating recovery after early cortical injury. Rats with medial prefrontal cortex (MFC), posterior parietal cortex (PPC), or sham lesions at postnatal day 3 (P3) received one of three variations of FGF-2 treatment: postnatal FGF-2 that was either pre-mixed or prepared daily, or prenatal FGF-2, and tested in adulthood. Behavioral tests used were: 1) the Morris Water task and, 2) the Whishaw Tray Reaching task. The level of functional recovery attained was dependent on FGF-2 preparation and the developmental period. MFC lesion rats showed good recovery but there was a differntial effect of pre and postnatal FGF-2 that appeared to be related to task. PPC rats showed greater recovery after postnatal rather than prenatal treatment. Anatomical changes were restricted to groups with relatively good functional recovery. These findings suggest a multifunctional role of FGF-2 in the injured brain. / xvi, 223 leaves : ill. ; 29 cm.

Bibliography: leaves 105-136. / vi, 136, [73] leaves, [13] leaves of plates : ill. (some col) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry, 1992

Diss. (sammanfattning) Stockholm : Karol. inst., 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 5 uppsatser.

Thesis (M.Sc.)--Memorial University of Newfoundland, Faculty of Medicine, 1999. / Typescript. Bibliography: leaves 97-117.