Academic literature on the topic 'Flightless protein'
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Journal articles on the topic "Flightless protein"
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Davy, D. A., H. D. Campbell, S. Fountain, D. de Jong, and M. F. Crouch. "The flightless I protein colocalizes with actin- and microtubule-based structures in motile Swiss 3T3 fibroblasts: evidence for the involvement of PI 3-kinase and Ras-related small GTPases." Journal of Cell Science 114, no. 3 (February 1, 2001): 549–62. http://dx.doi.org/10.1242/jcs.114.3.549.
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The flightless I protein contains an actin-binding domain with homology to the gelsolin family and is likely to be involved in actin cytoskeletal rearrangements. It has been suggested that this protein is involved in linking the cytoskeletal network with signal transduction pathways. We have developed antibodies directed toward the leucine rich repeat and gelsolin-like domains of the human and mouse homologues of flightless I that specifically recognize expressed and endogenous forms of the protein. We have also constructed a flightless I-enhanced green fluorescent fusion vector and used this to examine the localization of the expressed protein in Swiss 3T3 fibroblasts. The flightless I protein localizes predominantly to the nucleus and translocates to the cytoplasm following serum stimulation. In cells stimulated to migrate, the flightless I protein colocalizes with beta-tubulin- and actin-based structures. Members of the small GTPase family, also implicated in cytoskeletal control, were found to colocalize with flightless I in migrating Swiss 3T3 fibroblasts. LY294002, a specific inhibitor of PI 3-kinase, inhibits the translocation of flightless I to actin-based structures. Our results suggest that PI 3-kinase and the small GTPases, Ras, RhoA and Cdc42 may be part of a common functional pathway involved in Fliih-mediated cytoskeletal regulation. Functionally, we suggest that flightless I may act to prepare actin filaments or provide factors required for cytoskeletal rearrangements necessary for cell migration and/or adhesion.
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de Couet, H. G., K. S. Fong, A. G. Weeds, P. J. McLaughlin, and G. L. Miklos. "Molecular and mutational analysis of a gelsolin-family member encoded by the flightless I gene of Drosophila melanogaster." Genetics 141, no. 3 (November 1, 1995): 1049–59. http://dx.doi.org/10.1093/genetics/141.3.1049.
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Abstract The flightless locus of Drosophila melanogaster has been analyzed at the genetic, molecular, ultrastructural and comparative crystallographic levels. The gene encodes a single transcript encoding a protein consisting of a leucine-rich amino terminal half and a carboxyterminal half with high sequence similarity to gelsolin. We determined the genomic sequence of the flightless landscape, the breakpoints of four chromosomal rearrangements, and the molecular lesions in two lethal and two viable alleles of the gene. The two alleles that lead to flight muscle abnormalities encode mutant proteins exhibiting amino acid replacements within the S1-like domain of their gelsolin-like region. Furthermore, the deduced intron-exon structure of the D. melanogaster gene has been compared with that of the Caenorhabditis elegans homologue. Furthermore, the sequence similarities of the flightless protein with gelsolin allow it to be evaluated in the context of the published crystallographic structure of the S1 domain of gelsolin. Amino acids considered essential for the structural integrity of the core are found to be highly conserved in the predicted flightless protein. Some of the residues considered essential for actin and calcium binding in gelsolin S1 and villin V1 are also well conserved. These data are discussed in light of the phenotypic characteristics of the mutants and the putative functions of the protein.
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Campbell, H. D., T. Schimansky, C. Claudianos, N. Ozsarac, A. B. Kasprzak, J. N. Cotsell, I. G. Young, H. G. de Couet, and G. L. Miklos. "The Drosophila melanogaster flightless-I gene involved in gastrulation and muscle degeneration encodes gelsolin-like and leucine-rich repeat domains and is conserved in Caenorhabditis elegans and humans." Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11386–90. http://dx.doi.org/10.1073/pnas.90.23.11386.
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Mutations at the flightless-I locus (fliI) of Drosophila melanogaster cause flightlessness or, when severe, incomplete cellularization during early embryogenesis, with subsequent abnormalities in mesoderm invagination and in gastrulation. After chromosome walking, deficiency mapping, and transgenic analysis, we have isolated and characterized flightless-I cDNAs, enabling prediction of the complete amino acid sequence of the 1256-residue protein. Data base searches revealed a homologous gene in Caenorhabditis elegans, and we have isolated and characterized corresponding cDNAs. By using the polymerase chain reaction with nested sets of degenerate oligonucleotide primers based on conserved regions of the C. elegans and D. melanogaster proteins, we have cloned a homologous human cDNA. The predicted C. elegans and human proteins are, respectively, 49% and 58% identical to the D. melanogaster protein. The predicted proteins have significant sequence similarity to the actin-binding protein gelsolin and related proteins and, in addition, have an N-terminal domain consisting of a repetitive amphipathic leucine-rich motif. This repeat is found in D. melanogaster, Saccharomyces cerevisiae, and mammalian proteins known to be involved in cell adhesion and in binding to other proteins. The structure of the maternally expressed flightless-I protein suggests that it may play a key role in embryonic cellularization by interacting with both the cytoskeleton and other cellular components. The presence of a highly conserved homologue in nematodes, flies, and humans is indicative of a fundamental role for this protein in many metazoans.
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Carpentier, Samuel J., Minjian Ni, Jeffrey M. Duggan, Richard G. James, Brad T. Cookson, and Jessica A. Hamerman. "The signaling adaptor BCAP inhibits NLRP3 and NLRC4 inflammasome activation in macrophages through interactions with Flightless-1." Science Signaling 12, no. 581 (May 14, 2019): eaau0615. http://dx.doi.org/10.1126/scisignal.aau0615.
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B cell adaptor for phosphoinositide 3-kinase (PI3K) (BCAP) is a signaling adaptor that activates the PI3K pathway downstream of B cell receptor signaling in B cells and Toll-like receptor (TLR) signaling in macrophages. BCAP binds to the regulatory p85 subunit of class I PI3K and is a large, multidomain protein. We used proteomic analysis to identify other BCAP-interacting proteins in macrophages and found that BCAP specifically associated with the caspase-1 pseudosubstrate inhibitor Flightless-1 and its binding partner leucine-rich repeat flightless-interacting protein 2. Because these proteins inhibit the NLRP3 inflammasome, we investigated the role of BCAP in inflammasome function. Independent of its effects on TLR priming, BCAP inhibited NLRP3- and NLRC4-induced caspase-1 activation, cell death, and IL-1β release from macrophages. Accordingly, caspase-1–dependent clearance of a Yersinia pseudotuberculosis mutant was enhanced in BCAP-deficient mice. Mechanistically, BCAP delayed the recruitment and activation of pro–caspase-1 within the NLRP3/ASC preinflammasome through its association with Flightless-1. Thus, BCAP is a multifunctional signaling adaptor that inhibits key pathogen-sensing pathways in macrophages.
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Takimoto, Masato. "Multidisciplinary Roles of LRRFIP1/GCF2 in Human Biological Systems and Diseases." Cells 8, no. 2 (January 31, 2019): 108. http://dx.doi.org/10.3390/cells8020108.
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Leucine Rich Repeat of Flightless-1 Interacting Protein 1/GC-binding factor 2 (LRRFIP1/GCF2) cDNA was cloned for a transcriptional repressor GCF2, which bound sequence-specifically to a GC-rich element of epidermal growth factor receptor (EGFR) gene and repressed its promotor. LRRFIP1/GCF2 was also cloned as a double stranded RNA (dsRNA)-binding protein to trans-activation responsive region (TAR) RNA of Human Immunodeficiency Virus-1 (HIV-1), termed as TAR RNA interacting protein (TRIP), and as a binding protein to the Leucine Rich Repeat (LRR) of Flightless-1(Fli-1), termed as Flightless-1 LRR associated protein 1 (FLAP1) and LRR domain of Flightless-1 interacting Protein 1 (LRRFIP1). Subsequent functional studies have revealed that LRRFIP1/GCF2 played multiple roles in the regulation of diverse biological systems and processes, such as in immune response to microorganisms and auto-immunity, remodeling of cytoskeletal system, signal transduction pathways, and transcriptional regulations of genes. Dysregulations of LRRFIP1/GCF2 have been implicated in the causes of several experimental and clinico-pathological states and the responses to them, such as autoimmune diseases, excitotoxicity after stroke, thrombosis formation, inflammation and obesity, the wound healing process, and in cancers. LRRFIP1/GCF2 is a bioregulator in multidisciplinary systems of the human body and its dysregulation can cause diverse human diseases.
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O’Rourke, Allison R., and Jessica A. Hamerman. "Flightless-1 promotes lung CD103+ cDC phagocytosis and migration." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 69.14. http://dx.doi.org/10.4049/jimmunol.204.supp.69.14.
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Abstract Dendritic cells are specialized antigen-presenting cells integral for bridging the innate and adaptive immune responses. Critical to dendritic cell function is the need for a dynamic actin cytoskeleton. Flightless-1 is an actin capping protein linked to processes vital for dendritic cell immune functions including cell extension formation, phagocytosis, cell migration, and cell adhesion. Consistent with an important role in actin dynamics, whole body Flightless-1 knockouts are embryonic lethal. To enable further study of Flightless-1 in the immune response, we made mice with dendritic cell Flightless-1 deficiency using the CD11c-CRE driver. Homeostatic cDC1 and cDC2 populations in the spleen and lymph nodes were unchanged in DC-Flightless-1 knockouts relative to control animals. However, DC-Flightless-1 ablation led to a developmental disadvantage when in competition with WT DCs in mixed bone marrow chimeras. Upon LPS challenge in the airways, the Flightless-deficient cDC1 population showed reduced phagocytosis and migration to the lung draining lymph nodes. The DC migratory defect in the absence of Flightless-1 was supported by decreased CCR7 expression in both cDC1 and cDC2 populations. We hypothesize that the observed defects in phagocytosis and migration in Flightless-1-deficient dendritic cells are due to an altered actin cytoskeleton, which may also affect other actin-based immune structures. Current experiments are testing this hypothesis, and investigating the ability of Flightless-deficient DC to prime T cell responses.
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Navarro-Payá, David, Ilona Flis, Michelle A. E. Anderson, Philippa Hawes, Ming Li, Omar S. Akbari, Sanjay Basu, and Luke Alphey. "Targeting female flight for genetic control of mosquitoes." PLOS Neglected Tropical Diseases 14, no. 12 (December 3, 2020): e0008876. http://dx.doi.org/10.1371/journal.pntd.0008876.
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Aedes aegypti Act4 is a paralog of the Drosophila melanogaster indirect flight muscle actin gene Act88F. Act88F has been shown to be haploinsufficient for flight in both males and females (amorphic mutants are dominant). Whereas Act88F is expressed in indirect flight muscles of both males and females, expression of Act4 is substantially female-specific. We therefore used CRISPR/Cas9 and homology directed repair to examine the phenotype of Act4 mutants in two Culicine mosquitoes, Aedes aegypti and Culex quinquefasciatus. A screen for dominant female-flightless mutants in Cx. quinquefasciatus identified one such mutant associated with a six base pair deletion in the CxAct4 coding region. A similar screen in Ae. aegypti identified no dominant mutants. Disruption of the AeAct4 gene by homology-dependent insertion of a fluorescent protein marker cassette gave a recessive female-flightless phenotype in Ae. aegypti. Reproducing the six-base deletion from Cx. quinquefasciatus in Ae. aegypti using oligo-directed mutagenesis generated dominant female-flightless mutants and identified additional dominant female-flightless mutants with other in-frame insertions or deletions. Our data indicate that loss of function mutations in the AeAct4 gene are recessive but that short in-frame deletions produce dominant-negative versions of the AeAct4 protein that interfere with flight muscle function. This makes Act4 an interesting candidate for genetic control methods, particularly population-suppression gene drives targeting female viability/fertility.
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Straub, K. L., M. C. Stella, and M. Leptin. "The gelsolin-related flightless I protein is required for actin distribution during cellularisation in Drosophila." Journal of Cell Science 109, no. 1 (January 1, 1996): 263–70. http://dx.doi.org/10.1242/jcs.109.1.263.
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We have analysed the developmental defects in Drosophila embryos lacking a gelsolin-related protein encoded by the gene flightless I. Such embryos have previously been reported to gastrulate abnormally. We now show that the most dramatic defects are seen earlier, in actin-dependent events during cellularisation of the syncytial blastoderm, a process with similarities to cytokinesis. The blastoderm nuclei migrate to the periphery of the egg normally but lose their precise cortical positioning during cellularisation. Cleavage membranes are initially formed, but invaginate irregularly and often fail to close at the basal end of the newly formed cells. The association of actin with the cellularisation membranes is irregular, suggesting a role for flightless I in the delivery of actin to the actin network, or in its stabilisation.
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Arora, P. D., K. Nakajima, A. Nanda, A. Plaha, A. Wilde, D. B. Sacks, and C. A. McCulloch. "Flightless anchors IQGAP1 and R-ras to mediate cell extension formation and matrix remodeling." Molecular Biology of the Cell 31, no. 15 (July 15, 2020): 1595–610. http://dx.doi.org/10.1091/mbc.e19-10-0554.
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Lee, Young-Ho, Hugh D. Campbell, and Michael R. Stallcup. "Developmentally Essential Protein Flightless I Is a Nuclear Receptor Coactivator with Actin Binding Activity." Molecular and Cellular Biology 24, no. 5 (March 1, 2004): 2103–17. http://dx.doi.org/10.1128/mcb.24.5.2103-2117.2004.
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ABSTRACT Hormone-activated nuclear receptors (NR) activate transcription by recruiting multiple coactivator complexes to the promoters of target genes. One important coactivator complex includes a p160 coactivator (e.g., GRIP1, SRC-1, or ACTR) that binds directly to activated NR, the histone acetyltransferase p300 or CBP, and the arginine-specific histone methyltransferase CARM1. We previously demonstrated that the coactivator function of CARM1 depends both on the methyltransferase activity and on additional unknown proteins that bind to CARM1. In this study a yeast two-hybrid screen for proteins that bind CARM1 identified the protein Flightless I (Fli-I), which has essential roles in Drosophila and mouse development. Fli-I bound to CARM1, GRIP1, and NRs and cooperated synergistically with CARM1 and GRIP1 to enhance NR function. Fli-I bound poorly to and did not cooperate with PRMT1, a CARM1-related protein arginine methyltransferase that also functions as an NR coactivator. The synergy between GRIP1, CARM1, and Fli-I required the methyltransferase activity of CARM1. The C-terminal AD1 (binding site for p300/CBP) and AD2 (binding site for CARM1) activation domains of GRIP1 contributed to the synergy but were less stringently required than the N-terminal region of GRIP1, which is the binding site for Fli-I. Endogenous Fli-I was recruited to the estrogen-regulated pS2 gene promoter of MCF-7 cells in response to the hormone, and reduction of endogenous Fli-I levels by small interfering RNA reduced hormone-stimulated gene expression by the endogenous estrogen receptor. A fragment of Fli-I that is related to the actin binding protein gelsolin enhanced estrogen receptor activity, and mutations that reduced actin binding also reduced the coactivator function of this Fli-I fragment. These data suggest that Fli-I may facilitate interaction of the p160 coactivator complex with other coactivators or coactivator complexes containing actin or actin-like proteins.
Dissertations / Theses on the topic "Flightless protein"
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Seward, Matthew Edward. "Calcium/Calmodulin Dependent Protein Kinase Type-II Associates with Flightless-I to Influence its Nuclear Localization." VCU Scholars Compass, 2006. http://hdl.handle.net/10156/2132.
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Ruzehaji, Nadira. "The role of cytoskeletal protein flightless I (FLII) in diabetic wound healing." Thesis, 2013. http://hdl.handle.net/2440/95246.
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Skin lesions and ulcerations are common and severe complications of diabetes. A significant proportion of these wounds fail to respond to conventional treatment, hence amputation is a feared outcome of diabetes. Overexpression of Flightless (Flii) inhibits wound healing and ablation of Flii using specific neutralising monoclonal antibodies (FnAb) enhances cellular proliferation and migration. It was therefore hypothesized that decreasing Flii expression in diabetic wounds would create a permissive environment for cellular proliferation, enhanced neovascularization, and improved healing outcomes. The aim of this study was to determine whether genetic Flii gene knockdown or treatment with FnAb were effective in improving diabetic wound repair. A mouse model of diabetes was used in which type 1 diabetes was induced using streptozotocin. Diabetes was subsequently induced in low (Flii⁺ʹ⁻), normal (WT) and high (FliiTg/Tg) [Tg/Tg in superscript] mice. Full-thickness dorsal wounds were created and it was found that these wounds healed more rapidly when Flii gene expression was decreased. Further studies revealed that this improved healing was accompanied by a robust pro-angiogenic response with significantly elevated von Willebrand factor and VEGF positive endothelial cell infiltration. In a separate study, wounds in WT diabetic mice were injected intradermally with FnAb and here too improved healing was observed with significantly increased rate of re-epithelialisation compared with placebo control. We investigated the angiogenic response of FnAb both in vitro and in vivo. FnAb enhanced capillary tube formation in human umbilical vein endothelial cells (HUVEC) and promoted formation of functional neovasculature in vivo. Mice with reduced Flii also showed increased numbers of mature blood vessels using an in vivo Matrigel plug assay with increased recruitment of α-SMA positive cells and improved tight junction aiding cell to cell attachments. In conclusion, reducing Flii levels in wounds either genetically or using neutralising antibodies promotes wound healing in diabetic mice by enhancing epithelialisation and improving angiogenic processes. Manipulating Flightless I may therefore be a potential approach for therapeutic intervention in the treatment of the diabetic foot.Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2013
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Kopecki, Zlatko. "Effect of Flightless protein on skin architecture, cellular responses and Epidermolysis Bullosa." Thesis, 2011. http://hdl.handle.net/2440/69704.
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Wound healing is an area of largely unmet medical need with patients often relying on wound management practice rather than specific therapies. Recent research in our laboratory has identified a cytoskeletal protein Flightless (Flii) as a negative regulator of wound healing. This highly conserved protein is important in development and has a unique structure allowing it to act as a multifunctional protein. Flii expression increases in response to wounding, inhibiting cellular migration and proliferation while its deficiency improves wound healing. The aim of this study was to investigate the effect of differential Flii expression on skin architecture, cellular responses during wound healing, adhesionmediated cell signaling and skin blistering associated with the genetic skin disorder Epidermolysis Bullosa (EB). Chapter 3 of this thesis describes the effect of differential Flii expression on skin architecture and formation of hemidesmosomes which anchor the skin layers. Using primary fibroblasts and keratinocytes with varying Flii expression this study investigated the effect of Flii expression on cellular adhesion, spreading and migration on different extracellular matrix substrates. The results presented in Chapter 3 also describe the effect of Flii neutralising antibodies on primary keratinocyte proliferation illustrating improved proliferation in response to decreased Flii expression. In Chapter 4 an incisional wound healing model was used to investigate the effect of differential Flii expression on different components of hemidesmosomes. Flightless was
shown to regulate hemidesmosome formation through its effects on integrin-mediated cellular adhesion and migration. Using immunoprecipitation studies, Flii association with structural and signaling proteins present at the dermal-epidermal junction was investigated. Flii was found to form a cytoskeletal complex with talin, vinculin and paxillin suggesting its role in downstream signaling. The association of Flii with paxillin was further investigated in Chapter 5 where the effect of Flii over-expression on fibroblast adhesion and formation of adhesion structures was examined. Flii over-expression inhibited paxillin activation and the turnover of adhesion structures through down regulation of signaling proteins involved in cell adhesion signaling pathways. Chapter 6 of this thesis summarises the effect of Flii in skin blistering by utilizing both human samples and two mouse models of Epidermolysis Bullosa. Flii expression is significantly increased in response to skin blistering and its effects on integrin mediated cellular adhesion, migration and type VII collagen expression make Flii a negative contributor to blister formation. Decreasing Flii expression genetically or using neutralizing antibodies reduces skin blistering, improves cellular adhesion and decreases TGF-β mediated collagen contraction. In summary, Flii adversely affects skin strength and blister formation. Using a multidi-mensional approach of both in vitro and in vivo methodologies, human tissue and animal models this thesis reveals several novel findings and contributes to better understanding the involvement of Flii in both maintaining skin homeostasis and regulating wound repair. Flii is a novel target for development of mechanistic based therapy for improved wound healing. Findings presented in this thesis may open doors to significant changes in clinical practice and contribute to better therapeutic design by which would healing of blisters in patients with Epidermolysis Bullosa might be improved.Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2011
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Cameron, Alexander MacGregor. "The role of flightless protein in hypertrophic scarring and its potential as a target for a novel therapy." Thesis, 2018. http://hdl.handle.net/2440/117908.
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Hypertrophic scarring is a poorly understood condition which affects the lives of millions of people around the world annually. Despite its common occurrence following burn injury, trauma or surgery the present treatments are of limited efficacy. Research over the past decade in the Cowin laboratory has identified Flightless (Flii), a highly conserved cytoskeletal protein, as a negative regulator of wound healing. Wounding leads to an increased expression of Flii, while Flii has been shown to inhibit cellular migration and proliferation. Reducing Flii in vivo leads to improved wound healing. The aim of this study was to investigate the role of Flii in the fibroproliferative process underlying hypertrophic scarring. Chapter three shows for the first time that Flii expression in increased in human burn and hypertrophic scar tissue. Chapter four details the development of a novel murine model of hypertrophic scarring. Previous animal models have focused on reproducing the clinical characteristics of the human hypertrophic scar, which often required significant derangement of the animal immune response. The novel model used bleomycin to stimulate the fibroproliferative process that underlies hypertrophic scarring. Results in this chapter use histology and immunohistochemistry to verify the bleomycin model as a valid model of hypertrophic scarring. Chapter five uses the bleomycin mode to demonstrate that Flii is a key determinant of the extent of fibroproliferation that underlies hypertrophic scarring. Increasing Flii genetically in this animal model leads to increased dermal thickening and increases in key determinants of hypertrophic scarring, such as myofibroblasts, transforming growth factorβ-1 (TGFβ-1) and scar collagen composition. Decreasing Flii genetically causes a reduction in hypertrophic scarring using the same measures. Decreasing Flii using a monoclonal antibody therapy in the bleomycin model also led to a reduction in hypertrophic scarring, confirming Flii as a potential target for a novel therapy for hypertrophic scarring. Chapter six investigates potential mechanisms for the findings observed in previous chapters by using in vivo techniques. Focusing on the fibroblast, the key cell type in fibroproliferation, immunocytochemistry and cell migration assays, were used to show that decreasing Flii genetically or using a monoclonal antibody, reverses the fibroblast-myofibroblast phenotypic change that characterizes fibroproliferartive pathology. Flii appears to be a key determinant of the fibroproliferative process underlying hypertrophic scarring. This study uses human tissue, a novel small animal model and in vivo techniques to demonstrate this and identify Flii as a potential target for a novel therapy to reduce or prevent hypertrophic scarring.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2018
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Chan, Huater. "Roles of actin remodeling proteins, gelsolin and Flightless-I in epidermal wound healing." Thesis, 2011. http://hdl.handle.net/2440/72723.
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