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Dissertations / Theses on the topic 'Integrins'

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Published: 4 June 2021
Last updated: 6 July 2024

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1

Câmara, Joana. "Integrins and myelination." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613217.

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2

Mutz, Diana. "Identifizierung von Bindungspartnern des cytosolischen Teils der [alpha]3-Integrin-Untereinheit [Alpha3-Integrin-Untereinheit] und die Aufklärung ihrer Rolle bei der Funktion des [alpha]3[beta]1-Integrins [Alpha3beta1-Integrins]." [S.l. : s.n.], 2004. http://www.diss.fu-berlin.de/2004/214/index.html.

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3

Bao, Wenjie. "Role of integrin signaling in cell proliferation and survival /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-394-9/.

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4

Hall, P. E. "Integrins and neural stem cells." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599860.

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Extracellular matrix (ECM)-rich basal laminae are an important component of other stem cell niches and thus are likely to form part of the NSC niche. Interactions with the ECM are mediated manly by cell surface heterodimers called integrins. β1 integrins have been implicated in maintaining human epidermal stem cells, and their elevated expression has allowed the enrichment of human prostate epithelial stem cells from transit amplifying populations. My work has focused on the role of the ECM and its receptors in the mammalian CNS stem cell niche. Initial experiments examined the conditions necessary to grow human NSCs under clonal conditions, before using these findings to demonstrate that these cells express higher levels of integrin α6β1 then progenitor or differential cell types. This led to the question of the role of integrins in NSC behaviour, which was investigated in vitro with human and murine tissue using integrin activating/blocking antibodies together with ECM molecules. Laminin-211, an α6β1 ligand, was found to increase NSC survival in an integrin-dependent manner. However, activation of integrin β1 did not recapitulate these results, indicating that integrin β1 is necessary, but not sufficient, for laminin to increase survival. Finally, in utero injections of the integrin activating/block antibodies into the lateral ventricle of embryonic day 15 (E15) embryos were conducted in order to examine the role of integrins in the in vivo stem cell niche. In conclusion, the findings indicate that integrins are highly expressed by neural stem cells and that integrins function in vitro and in vivo to influence stem cell behaviour.
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5

Petrie, Timothy Andrew. "Biomimetic integrin-specific surface to direct osteoblastic function and tissue healing." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/29628.

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Thesis (Ph.D)--Biomedical Engineering, Georgia Institute of Technology, 2010.
Committee Chair: Andres Garcia; Committee Member: Andrew Lyon; Committee Member: Barbara Boyan; Committee Member: Johnna Temenoff; Committee Member: Todd McDevitt. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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6

Shekaran, Asha. "Beta 1 integrins in bone formation during development and engineering integrin-specific hydrogels for enhanced bone healing." Diss., Georgia Institute of Technology, 2013. http://hdl.handle.net/1853/51720.

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Healing large bone defects remains a clinical challenge. While autografts are the gold standard treatment for large bone defects, they are limited by availability and donor site pain. Growth factor treatments such as BMP therapy provide a promising alternative but are expensive and present clinical safety concerns, primarily due to delivery of BMPs at supraphysiological doses. Integrins are ECM receptors which mediate crucial cell functions such as adhesion and differentiation. Therefore, understanding the role of integrins in bone formation and directing desired interactions may enable modulation of host cell functions for therapeutic applications. In this work, beta 1 integrins were deleted in osteolineage cells of transgenic mice at three different stages of differentiation to elucidate their role in bone development. We also engineered bioartificial PEG-based matrices which target the pro-osteogenic alpha 2 beta 1 integrin to promote bone healing. Conditional deletion of beta 1 integrins in osteochondroprogenitor cells under the Twist 2 promoter resulted in severe pre-natal skeletal mineralization defects and embryonic lethality. Targeted deletion of beta 1 integrins in osterix-expressing osteoprogenitors resulted in growth abnormalities, reduced calvarial mineralization, impaired femur development, and tooth defects. However, mice lacking beta 1 integrins in osteocalcin-expressing osteoblasts and osteocytes displayed only a mild skeletal phenotype, indicating that beta 1 integrins play an important role in early skeletal development, but are not required for mature osteoblast function. PEG hydrogels functionalized with the integrin-specific GFOGER ligand enhanced bone regeneration, induced defect bridging in combination with low doses of rhBMP-2 and stimulated improved bone healing compared collagen sponges, which are the clinical standard delivery vector for BMP-2 therapy. These results suggest that treatment with bioartificial integrin-specific PEG hydrogels may be a promising clinical strategy for bone regeneration in large bone defects.
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7

Savaris, Ricardo Francalacci. "Níveis de integrina avb3 no endométrio de mulheres usuárias do DIU T200." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 1999. http://hdl.handle.net/10183/184861.

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Objetivo: Medir a expressão da integrina av~3 no endométrio de mulheres usuárias do DIUT200. Desenho: Estudo observacional controlado. Local realizado: Centro de saúde secundário e laboratório universitário. Pacientes: Treze mulheres sadias e férteis (controles) e treze usuárias do DIUT200 (casos). lntervençao: Biópsia endometrial realizada entre o 6°-1 0° dia pós-ovulatório do ciclo menstrual. Principal Desfecho Avaliado: A expressão da integrina av~3 através do HSCORE em amostras endometriais criopreservadas. Resultados: O HSCORE das usuárias do DIUT200 foi 0,9 ± 0,7 (média± DP), enquanto que o dos controles foi 2,13 ± 0,7 (média ± DP) (p = 0.001 Teste-t de Student). Todos os controles foram positivos para a expressão da integrina av~3. mas as usuárias do DIUT200 não apresentou positivdade para a integrina av~3 em 38,5% dos casos (p = 0,03 Teste Exato de Fisher). Conclusao: Os resultados apoiam a teoria que o DIUT200 de cobre também tem um mecanismo de ação que interfere diretamente com a receptividade uterina e a implantação.
Objective: To measure the expression of avf33 integrin in the endometrium of IUDT200 users. Design: Observational controlled study Setting: Secondary health care center and University laboratory Patients: Thirteen healthy fertile women (contrais) and thirteen IUDT200 users (cases). lntervention: Endometrial biopsy on postovulatory day 6-1 O of the menstrual cycle. Main Outcome Measure: The expression of avJ33 by HSCORE on cryopreserved endometrial sections. Results: The HSCORE for IUD users was 0.9 ± 0.7 (mean ± SEM), while for contrais was 2.13 ± 0.7 (mean ±SEM) (p < 0.001 Teste-t de Student). Ali contrais were positiva for avJ33, but women with IUD did not express avl33 integrin in 38.5% of the cases (p < 0.03 Fisher's exact test). Conclusion: These results support the theory that copper IUD T200 also has a mechanism of action that is directed at interference with uterine receptivity and implantation.
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8

Eshghi, Shawdee. "The roll of integrins in hematopoiesis." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/39905.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2007.
Includes bibliographical references (p. 113-123).
Hematopoietic stem cells (HSCs) hold great promise for the treatment of disease. The rare frequency at which HSCs occur in the bone marrow under homeostatic conditions is a limiting factor in both their study and clinical use. ex vivo expansion of these cells is therefore a necessary step to maximizing their potential. In this thesis I explore the concept that signals from the extracellular matrix can direct differentiation, survival and self-renewal decisions in hematopoietic cells, and thus can provide a foundation for the design of ex vivo expansion strategies. This work is focused on the role integrins, the major class of cell-extracellular matrix adhesion molecules, play in mediating these signals to hematopoietic cells at two developmental stages. In the erythroid lineage, I show that expansion of committed erythroid progenitors is regulated by growth factor and integrin-mediated signals in temporally distinct regimes. I establish a biologically relevant role for [alpha]401 but not [alpha]501 integrins in erythropoiesis and provide evidence that erythroid differentiation and expansion are regulated by separate processes.
(cont.) In the study of uncommitted HSCs, I identify several integrin subunits that are differentially expressed on highly purified HSC populations that correlate with long term repopulating ability. One of these subunits, [alpha]2 integrin, specifically mediates adhesion of HSCs to bone marrow extracellular matrix proteins, thereby providing a potential mechanism for stem cell self-renewal. This work establishes that integrin-mediated interactions between hematopoietic cells and the extracellular matrix are dynamic and provide important developmental cues.
by Shawdee Eshghi.
Ph.D.
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9

Douglass, Wendy A. "The structure and function of integrins." Thesis, University of Oxford, 1997. http://ora.ox.ac.uk/objects/uuid:cfdfd40c-b350-4500-83e4-2650f9fe455d.

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Integrins are a family of αβ heterodimeric cell surface glycoproteins formed by the noncovalent association of a specific integrin α and β subunit. At present 16 different integrin α subunits and 8 different integrin β subunits have been identified, which can associate in various combinations to produce over 20 different integrin αβ heterodimeric receptors. The leukocyte integrins LFA-1 (αLβ2, CD11a/CD18), Mac-1 (αMβ2, CD11b/CD18) and p150,95 (αXβ2, CD11c/CD18) are formed by the non-covalent association of the αL, αM or αX subunits with the β2 subunit. In order to determine the regions of the β2 subunit which are involved in its heterodimeric interaction with the αL, αM and αX subunits, eight variant β2 subunits were analysed for their ability to form LFA-1, Mac-1 and p150,95 heterodimeric complexes. Three chimeric β2/β1 subunits: β2V1, β2V12 and β2NS1, and three analogous chimeric β2/β7 subunits: β2V7, β2V72 and β2NS7, as well as a soluble and a truncated β2 subunit: β2sol and β2tr, were studied. All of the variant β2 subunits retained the ability to associate with the αL subunit, suggesting that the N-terminal 436 amino acids of the β2 subunit are sufficient to provide the specificity for LFA-1 heterodimer formation. In contrast, all the β2 variants associated inefficiently with the αM and αX subunits, suggesting that the heterodimeric interactions between the α and β subunits in Mac-1 and p150,95 are more extensive, and perhaps more complicated than those in LFA-1. The ability of the modified LFA-1 heterodimers formed with the variant β2 subunits to bind to the LFA-1 ligand ICAM-1 was also studied. All of the modified LFA-1 receptors retained the ability to bind to ICAM-1, suggesting that in LFA-1, the ICAM-1 binding site in the β2 subunit must be located within its N-terminal 436 amino acids. In addition, unlike the wildtype LFA-1 receptor, all of the modified LFA-1 receptors were constitutively active with respect to ICAM-1 binding. It therefore appears that specific interactions between different regions of the β2 subunit are required to constrain the LFA-1 receptor in its inactive, resting state, and that disruption of any one of these intramolecular interactions results in release of the receptor into its high affinity ligand binding conformation. This "constraint model" for the regulation of LFA-1 activity may also be applicable to other integrins. Analysis of a number of mutant β2 subunits carrying leukocyte adhesion deficiency (LAD) mutations, and their ability to form LFA-1, Mac-1 and p150,95 heterodimers, provided results consistent with those obtained with the variant β2 subunits.
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10

Divekar, Devina. "Integrins in muscle disease and repair." Thesis, University of East Anglia, 2014. https://ueaeprints.uea.ac.uk/54271/.

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Integrin α7β1 plays an important role in maintaining adult skeletal muscle integrity and like dystrophin, provides anchorage and bidirectional signaling as a laminin receptor. The expression of α7β1 integrin was upregulated upon dystrophin deficiency arguing for the molecular compensation and thus considered as potential candidate for treatment of Duchenne Muscular Dystrophy (DMD). The existence of developmentally regulated alternative splice variants makes the α7β1 integrin a complex integrin to study its function in skeletal muscle. In this study we show that increased levels of the adult extracellular variant X2 interfere with muscle integrity, while the presence of embryonic integrin α7 extracellular variant X1 results in normal skeletal muscle architecture. Furthermore, detailed analysis of mdxα7tg mice suggests that overexpression of integrin α7 made no difference on the dystrophic phenotype, in fact mdx α7X2 mice show a more severe phenotype compared to mdx mice. Our study also shed light on the importance of integrin α5 during the development of the skeletal muscle by means of generating conditional knockout (cKO) mice using HSA-Cre and Pax3-Cre promoter systems. Our findings show no obvious difference in the Itga5 cKO when the HSA promoter drives Cre recombinase, however conditional loss under the control of the Pax3 promoter leads perinatal lethality. In addition we investigate the dosage effect of integrin α5 in integrin α7 knockout (KO) mice to understand the cross talk between these two integrins and to correlate with previous data suggesting a gain of function phenotype by that existence of integrin α5 at the myotendinious junction (MTJ) in α7KO muscle (Nawrotzki et al.,2003) From our data we know that gene therapy with integrin α7 is a challenge and is not a suitable alternative to cure dystrophy, at least not in mdx mice, we therefore switch our focus on looking into cell based therapies for DMD by investigating the potential role of perivascular cells (PVCs) using transplantation experiments in mice by artificially inducing muscle damage.
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11

Rahman, Abdul. "Neonatale Alloimmunthrombozytopenie die Entwicklung von rekombinanten [alpha]II-1tnb[beta]3-Integrin-Isoformen [Alpha-IIb-Beta-3-Integrin-Isoformen] (HPA-1 Antigene) und funktionelle Untersuchung einer seltenen Punktmutation auf [beta]3-Integrins [Beta-3-Integrins] (Oea-Antigen) /." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968380859.

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12

Chakraborty, Arup R. "Differential expression of integrin [alpha]₃[beta]₁ and [alpha]₆[beta]₄ molecules on a panel of rat esophageal cell lines." Connect to this title online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=bgsu1131345357.

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13

Grundström, Gunilla. "Functional Studies of Collagen-Binding Integrins α2β1 and α11β1 : Interplay between Integrins and Platelet-Derived Growth Factor Receptors." Doctoral thesis, Uppsala University, Department of Medical Biochemistry and Microbiology, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3686.

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Integrins are heterodimeric cell surface receptors, composed of an α- and a β-subunit, which mediate cell-extracellular matrix (ECM) interactions. Integrins mediate intracellular signals in response to extracellular stimuli, and cooperate with growth factor and other cytokine receptors. Cells execute their differentiated functions anchored to an ECM. In this thesis functional properties of the two collagen-binding integrins α2β1 and α11β1 were studied. In addition, the impact of β1 cytoplasmic tyrosines in collagen-induced signalling was analyzed.

The integrin α11β1 is the latest identified collagen-binding integrin. In this study, tissue distribution of α11 mRNA and protein during embryonal development was explored, and the first α11β1-mediated cellular functions were established. Both α11 protein and mRNA were present in mesenchymal cells in intervertebral discs and around the cartilage of the developing skeleton. α11 protein was also detected in cornea keratinocytes. α11β1 mediated cation-dependent adhesion to collagen types I and IV and localized to focal adhesions. In addition, α11β1 mediated contraction of a collagen lattice and supported cell migration through a collagen substrate. PDGF-BB and FBS both stimulated α11β1-mediated contraction and directed migration.

Expression of β1Y783,795F in β1-null cells, prevents activation of FAK in response to fibronectin, and decreases cell migration. In this study, we investigated how this mutation affected α2β1-mediated functions in response to collagen. The β1 mutation impaired collagen gel contraction and prevented activation of FAK, Cas and Src on planar collagen, but not in collagen gels. PDGF-BB stimulated contraction via αvβ3, which also induced activation of Cas in collagen gels. The YY-FF mutation also abolished β1A-dependent downregulation of β3.

In the final study integrin-crosstalk during collagen gel contraction was investigated. In cells lacking collagen-binding integrins αvβ3 mediated contraction. Clustering of β1-integrins by antibodies and PDGF-BB stimulated αvβ3-mediated contraction in an ERK-dependent way. Expression of α2β1, but not α11β1, prevented αvβ3-mediated contraction. Contraction by α2β1 and α11β1 was ERK-independent.

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14

Walters, Susannah. "Structure and functional studies of leukocyte integrins." Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.410567.

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15

Buttery, P. "The role of integrins in oligodendrocyte differentiation." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597197.

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Oligodendrocytes and their precursors express a defined repertoire of integrin receptors, consisting of the heterodimers αvβ1, αvβ3, αvβ5, αvβ8 and a6β1. A role for the αvβ1 receptor has recently been defined in the migratory behaviour of oligodendrocyte precursors, and this project describes and extension of such work to examine the involvement of integrins in cellular differentiation and survival in this lineage. Using enriched populations of rodent oligodendrocyte precursors in simplified in vitro cell culture system several observations have been apparent: Firstly, there is evidence that β1 integrins are involved not only in migration of the precursors, but also in survival of the cells at all stages. In addition, morphological differentiation of the cells, which involves the elaboration of a complex meshwork of processes and subsequent myelin sheet formation, also turns out to be enhanced by a substrate of laminin-2, which is a potential ligand for the α6β1 integrin; correspondingly, it is shown that β1 integrins are also required for optimal morphological differentiation of the cells. Cellular differentiation is marked by a switch between an immature pattern of integrin expression (αvβ1, αvβ8 and α6β1) and a mature pattern of expression (αvβ3, αvβ5, αvβ8 and α6β1), and this switch is shown to be inhibited by the fibroblast growth factor, FGF-2. Upon withdrawal of FGF-2 therefore, the cells differentiate, exhibiting a burst of tyrosine phosphorylation; a group of tyrosine phosphorylated proteins are demonstrated to be associated with the β3 integrin subunit at this state, a subunit whose expression was inhibited by FGF-2. Finally, the different subunits β1, α6 and β5 show distinct spatial patterns of expression in differentiating cells, and evidence is presented to suggest the presence of an additional β1-associated α subunit, that is thus far unidentified.
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16

Poomsawat, Sopee. "Regulation of keratinocyte integrins by scatter factor." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343964.

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17

Lively, Julie C. (Julie Christina) 1971. "Beta 3 integrins : negative regulators of angiogenesis." Thesis, Massachusetts Institute of Technology, 2002. http://hdl.handle.net/1721.1/8386.

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Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Biology, 2002.
Includes bibliographical references (leaves 199-219).
A method was developed to isolate and purify primary murine endothelial cells from lung tissue (MLEC). The cells generated by this method were characterized by immuno-fluorescence detection and FACS analysis and expressed specific antigens including PECAM-1, ICAM-1, ICAM-2, VCAM-1 and VE-cadherin. Using this method, cells from wild-type and beta 3-integrin-deficient animals were purified and used to determine the specificity of a novel potential anti-angiogenic drug. This study shows that tumstatin, a fragment of the alpha 3 chain of collagen IV, inhibits proliferation, inhibits total protein synthesis and specifically inhibits CAP-dependent protein synthesis in MLEC. These effects do not occur when beta 3-null MLEC are treated with tumstatin or any of its derivatives. Nor do they occur in mouse embryonic fibroblasts which do express beta 3 integrin. The inhibition by tumstatin also occurs in in vivo angiogenesis assayed using a Matrigel plug insert. Similarly to in vitro assays, tumstatin failed to inhibit angiogenesis in beta 3 integrin-deficient animals. These results suggest that avf33 integrin is necessary but not sufficient for the activity of tumstatin. Further studies are required to identify avf33 integrin-associated factors in endothelial cells which determine tumstatin's endothelial cell specificity. Matrigel plug assays were also used to demonstrate that the loss of beta-3 integrin enhanced VEGF-induced angiogenesis. Results also show that VEGF-induced angiogenesis was enhanced in aortic ring explants from beta 3-null animals. These data suggest a new role for beta 3 integrin as a negative regulator of angiogenesis, both as a receptor for an endogenous inhibitory molecule and as an inhibitor of VEGF-induced angiogenesis.
by Julie C. Lively.
Ph.D.
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18

Zhang, Fang. "The regulation of conformation and binding kinetics of integrin alphaLbeta2." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/24678.

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Thesis (M. S.)--Biomedical Engineering, Georgia Institute of Technology, 2008.
Committee Chair: Zhu, Cheng; Committee Member: Babensee , Julia; Committee Member: Garcia, Andres; Committee Member: McIntire, Larry; Committee Member: Selvaraj, Periasamy; Committee Member: Springer, Timothy
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19

Alshammari, Fatemah O. F. O. "An immunohistopathological and functional investigation of β3 integrin antagonism as a therapeutic strategy in cancer : characterisation, development, and utilisation of preclinical cancer models to investigate novel β3 integrin anatgonists." Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/6327.

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Tumour cell dissemination is a major issue with the treatment of cancer, thus new therapeutic strategies which can control this process are needed. Antagonism of integrins highly expressed in tumours is one potential strategy. The integrins are transmembrane glycoprotein adhesive receptors. Two of the integrins, αVβ3 and αIIbβ3, are highly expressed in a number of tumours and induce bi-directional signalling through their interaction with extracellular matrix proteins, and growth factor receptors. Through this signalling they play an important role in a number of cellular processes that are involved in tumour dissemination such as tumour growth, migration, invasion, metastasis and angiogenesis. Dual αIIbβ3 and αVβ3 integrin antagonism will have a direct effect on β3-expressing tumour cells that leads to the inhibition of cell migration and dissemination. Furthermore, through targeting tumour cell interaction with endothelial cells and platelets, this will also lead to inhibition of angiogenesis and metastasis. The aim of this project was to characterise the expression of αVβ3 and αIIbβ3 integrin in a panel of tumour cell lines and in human tumour xenograft samples, and to develop and utilise cell-based models to investigate potential novel β3 antagonists. The expression of αV and β3 subunits was detected in xenograft tissue using immunoblotting techniques. A panel of cell lines of different tumour types including melanoma, prostate, breast, colon and non small cell lung carcinoma was then characterised for αVβ3 and αIIbβ3 integrin expression using immunoblotting and immunocytochemistry. Melanoma cell lines demonstrated the strongest αVβ3 expression. No αIIbβ3 integrin expression was seen in any of the cell lines evaluated. A selection of cell lines with varying αVβ3 expression were then used to develop a functional test for cell migration, the scratch wound healing assay. Migration of tumour cells that expressed αVβ3 integrin was inhibited by the known β3 antagonists, cRGDfV peptide and LM609 antibody. A panel of 12 potential novel β3 integrin antagonists was screened for cytotoxicity and activity in the validated scratch assay. ICT9055 was the most effective antagonist in inhibition of M14 cell migration as determined by the scratch assay, with an IC₅₀ of < 0.1 μM. Therefore the work presented in this thesis has established models and tools for evaluating potential novel β3 integrin antagonists, and identified a promising molecule to progress for further preclinical evaluation.
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20

Popov, Tzvetan. "Characterization of human mesenchymal stem cells by the appearance of integrins and functional analysis of collagen I-binding integrins." Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-127553.

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21

Möller, Laura Artoni. "Interação celular na placenta de gestações de bovinos clonados com especial ênfase às integrinas." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-02122009-091433/.

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Integrinas são glicoproteínas transmembrânicas envolvidas na adesão célula-célula e célula-proteina da matriz extracellular (ECM) que participam da migração e fusão de células trofoblásticas gigantes (TGC) com células do epitélio materno no placentoma bovino e interagem com inibidores teciduais de metalloproteinases (TIMPs), considerados importantes reguladores das metaloproteinases de matriz (MMPs), que são reconhecidas como passo limitande para ação de enzimas que atuam no remodelamento da ECM na implantação e na gestação. Uma vez que as integrinas são consideradas responsáveis pela manutenção da arquitetura tecidual e que as MMPs podem regular a degradação e a reconstituição da ECM necessária para a invasão do trofoblasto, temos como objetivo verificar uma possível relação das integrinas com alterações placentárias comumente observadas em gestações de animais clonados (SCNT). Para avaliar a funcionalidade placentária, a expressão do lactogênio placentário (PL) e do antígeno Ki-67 foram também verificadas. Placentomas bovinos foram coletados e divididos em 3 grupos: 1) início (n = 6) e 2) final (n = 3) da gestação de animais derivados de monta natural (n=9) e final da gestação de animais clonados (n=8), clones machos (n=4) e clones fêmeas (n=4). As proteínas foram localizadas por imuno-histoquímica indireta, exceto as subunidades de integrina α6, β1, αV e β3 que foram localizadas por imunofluorescência. A especificidade dos anticorpos e expressão protéica foi confirmada por Western blot e a expressão do RNAm foi avaliada por meio de RT-PCR e PCR em tempo real quantitativo. As células positivas para a laminina, TIMP-2, Ki-67 e lactogênio placentário (PL) foram quantificadas e para comparação entre os grupos. A proteína das subunidades α6 do receptor de integrina e β1 foi observada nos animais clonados e não clonados nos estromas materno e fetal e porção basal dos epitélios materno e fetal e foi co-localizada com a laminina. A proteína das subunidades αV e β3 do receptor de integrina foi observado nos estromas materno e fetal e foi co-localizado com a fibronectina. O TIMP-2 foi exclusivamente e especificamente localizado nas TGCs no início e final da gestação de animais clonados e não clonados, mas não houve diferença significativa em sua expressão. O PL apresentou a mesma localização do TIMP-2 em todos os grupos analisados. Houve diferença significativa (p<0,05) entre 270d e clones ao se comprar a expressão relativa do RNAm da subunidade de integrina β1 e do lactogênio placentário e ao se comparar a expressão protéica por western blot da laminina e do TIMP-2. Foi possível observar diferença significativa (p<0,05) entre o grupo controle e o grupo de animais clonados ao se quantificar o número de TGCs positivas para a laminina e para o lactogênio placentário. Apesar de algumas diferenças terem sido observadas na expressão de integrinas e de proteínas da ECM, sugere-se que a interação das integrinas com seus ligantes da ECM a termo não é um determinante da sobrevivência neonatal de bovinos clonados. Contudo, outros estudos são necessários para esclarecer se estas proteínas representam elementos chave na placentação de bovinos clonados em início de gestação. As diferenças observadas na expressão de integrinas e principalmente do PL entre clones fêmeas e machos sugerem possível influência de genes associados ao cromossomo sexual ou imprinting.
Integrins are transmembrane glycoproteins involved in cell-cell and cell-extracellular matrix (ECM) adhesion and signal transduction. They participate in the migration and fusion of trophoblast giant cells (TGC) with uterine epithelial cells in bovine placentomes, and interact with tissue inhibitors of metalloproteinases (TIMPs), considered important regulators of matrix metalloproteinases (MMPs). MMPs are rate-limiting enzymes degrading ECM proteins during tissue remodeling around embryo implantation, pregnancy and parturition. Since integrins are considered to be responsible for the maintenance of the architecture within tissues and MMPs may also regulate degradation and reconstitution of ECM required for trophoblast invasion, we aimed to verify a potential relation of integrins with common placental alterations observed in cloned animals (SCNT). To verify the placental functionality, expression of placental lactogen (PL) and Ki-67 antigen was also assessed. Bovine placentomes were collected and divided into 3 groups: 1) early and 2) late gestation derived from natural mating (n=9) and 3) late gestational bovine clones (n=8), also divided into male clones (n=4) and female clones (n=4). All proteins were localized by indirect immunohistochemistry except for integrin subunits α6, β1, αV and β3 that were shown by immunofluorescence. The antibody specificity and protein expression were confirmed by Western blot. Expression of mRNA was evaluated using RT-PCR and quantitative Real Time PCR. Positive cells for laminin, TIMP-2, Ki-67 and placental lactogen were quantified for comparisons among groups. The protein of integrin receptor subunits α6 and β1 was observed in both cloned and non-cloned animals in the fetal and maternal stroma and at the basal membrane of maternal and fetal epithelial cells, co-localized with laminin and with collagen IV. The integrin receptor subunits αV and β3 were observed in the fetal and maternal stroma, co-localized with fibronectin. TIMP-2 was specifically and exclusively localized in TGC in the early and term gestation in both cloned and non-cloned animals. PL has shown the same localization of TIMP-2 in all analyzed samples. Statistically significant differences (p<0,05) between term gestation of non-cloned and cloned animals were observed comparing the mRNA expression of integrin β1 subunit and placental lactogen and the protein expression of laminin and TIMP-2. There were also statistically significant differences (p<0,05) between non-cloned and cloned animals in the number of laminin and placental lactogen positive cells. Despite some differences in integrin and ECM proteins expression, our results suggest that the interaction between integrins and their ECM ligands in term gestation is not a determinant for the survival rate of newborn cloned calves. However further studies are necessary to elucidate if integrins represent key elements in the early placentation of SCNT bovines. The differences found in the integrin and principally in the placental lactogen expression between female and male cloned calves suggests the influence of sex-chromosome associated genes or imprinting.
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22

Kyumurkov, Alexander. "Role of ICAP-1 in integrins' dynamic regulation, mechanosensing and contractility of osteoblast cells." Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV057/document.

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L'ICAP-1 est impliqué dans la dynamique de l'intégrine et la génération de force en contrôlant l'endocytose de l'intégrine grâce à la scission dépendant de nm23 des puits endocycliques recouverts de chlatrine.L'ICAP-1 a été identifié comme un partenaire spécifique de l'intégrine b1 (Degani et al., 2002, Zhang et Hemler, 1999). Nous avons déjà montré que l'ICAP-1 est impliqué dans la réponse mécanisée aux cellules et la différenciation cellulaire d'une manière dépendante de l'intégrine b1 (Bouvard et al., 2007; Brunner et al., 2011; Faurobert et al., 2013; Millon-Frémillon et al. , 2008; Renz et al., 2015). Cependant, comme ICAP-1 est également capable d'adapter la migration cellulaire en réponse à la rigidité du substrat d'une manière indépendante de la β1-intégrine (Bouin et al., 2017), nous avons spéculé sur un rôle plus général de l'ICAP-1 dans l'adhésion cellulaire et dynamique d'adhérence focale. Pour cela, nous avons créé un environnement cellulaire où l'intégrine b1 et / ou l'ICAP-1 étaient absentes en utilisant quatre lignées cellulaires: les ostéoblastes WT, les cellules ostéoblastes KO de l'intégrine b1, les cellules ostéoblastes KAP ICAP-1 et les cellules ostéoblastes double KO b1 / ICAP-1 afin de surveiller le comportement de l'intégrine b3. Comme prévu, l'épuisement de l'intégrine b1 est associé à la perte d'étalement cellulaire et à la génération de force selon la mesure de la microscopie par force de traction. De manière surprenante, la suppression supplémentaire de ICAP-1 (b1 intégrine et ICAP-1 KO) conduit à la restauration de l'étalement cellulaire et de la génération de force qui dépend de l'intégrine b3. Ces forces médiées par l'intégrine b3 sont corrélées avec la diffusion lente de l'intégrine b3 dans les sites d'adhésion et le renouvellement lent de l'adhésion focale contenant l'intégrine b3 (FRAP / TIRF / vidéomicroscopie). Nous avons abordé la question de savoir si ICAP-1 pourrait réguler l'endocytose de l'intégrine b3 puisque ICAP-1 interagit avec nm23-H2 (Fournier et al., 2002), un nucléoside diphosphate kinases (NDPK) impliqué dans l'endocytose à médiation par dynamine en produisant du GTP à travers l'adénosine triphosphate (ATP) de conversion du diphosphate de guanosine (PIB) (Boissan et al., 2014). Nous montrons que la suppression de nm23 ou de dynamine ou de chlatrine dans les cellules épuisées dans l'intégrine b1 est capable d'imiter la perte combinée de l'intégrine b1 et de l'ICAP-1 en rétablissant l'étalement cellulaire, la génération de force et la dynamique de l'intégrine b3. Pour confirmer l'implication de l'ICAP-1 dans l'endocytose de l'intégrine b3, nous montrons que l'absorption de l'anticorps de l'intégrine b3 est efficacement bloquée dans les cellules épuisées dans ICAP-1. Nos résultats suggèrent que ICAP-1 pourrait être impliqué dans la dynamique de l'intégrine et la génération de force en contrôlant l'endocytose de l'intégrine grâce à la scission dépendant de nm23 des puits endocytaires de la couche de chlatrine
ICAP-1 is involved in integrin dynamics and force generation by controlling integrin endocytosis through nm23-dependent scission of endocytic chlatrin coated pits.ICAP-1 has been identified as a specific partner of b1 integrin (Degani et al., 2002; Zhang and Hemler, 1999). We have previously shown that ICAP-1 is involved in cell mechanoresponse and cell differentiation in a b1 integrin dependent manner (Bouvard et al., 2007; Brunner et al., 2011; Faurobert et al., 2013; Millon-Frémillon et al., 2008; Renz et al., 2015). However, as ICAP-1 is also able to adapt cell migration in response to substrate stiffness in a β1-integrin-independent manner (Bouin et al., 2017), we speculated on a more general role of ICAP-1 in cell adhesion and focal adhesion dynamics. For this purpose we have created cellular environment where b1 integrin and/or ICAP-1 were absent by using four cell lines: WT osteoblast, b1 integrin KO osteoblast cells, ICAP-1 KO osteoblast cells and double KO b1/ICAP-1 osteoblast cells in order to monitor b3 integrin behavior. As expected, depletion of b1 integrin is associated with the loss of cell spreading and force generation according traction force microscopy measurement. Surprisingly, the supplementary deletion of ICAP-1 (b1 integrin and ICAP-1 KO) leads to restoration of cell spreading and force generation which are dependent on b3 integrin. These b3 integrin-mediated forces are correlated with slow diffusion of b3 integrin within adhesion sites and slow turnover of b3 integrin containing focal adhesion (FRAP/TIRF/videomicroscopy). We addressed the question whether ICAP-1 might regulate b3 integrin endocytosis since ICAP-1 interacts with nm23-H2 (Fournier et al., 2002), a nucleoside diphosphate kinases (NDPKs) involved in dynamin-mediated endocytosis by producing GTP through adenosine triphosphate (ATP)–driven conversion of guanosine diphosphate (GDP) (Boissan et al., 2014). We show that the deletion of either nm23 or dynamin or chlatrin in cells depleted in b1 integrin is able to mimic the combined loss of b1 integrin and ICAP-1 by restoring cell spreading, force generation and b3 integrin dynamics. To confirm the involvement of ICAP-1 in b3 integrin endocytosis, we show that the b3 integrin antibody uptake is efficiently blocked in cells depleted in ICAP-1. Our results suggest that ICAP-1 might be involved in integrin dynamics and force generation by controlling integrin endocytosis through nm23-dependent scission of endocytic chlatrin coated pits
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23

Johnson, Casey P. "A Mathematical Model of Adhesion Interactions between Living Cells." Diss., CLICK HERE for online access, 2005. http://contentdm.lib.byu.edu/ETD/image/etd914.pdf.

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24

Elsharif, Amal A. M. "Functional Investigation of Dual αvβ3 and αllbβ3 Integrin Inhibition in Haematological and Solid Tumour Models." Thesis, University of Bradford, 2018. http://hdl.handle.net/10454/16883.

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Invasion and metastasis of cancer is the leading cause of increased mortality. In addition, haematological malignancies (leukaemia and lymphoma) are a significant cause of morbidity and mortality in both children and adults. Therefore, new treatments which will inhibit cancer progression are required. Integrin adhesion receptors, particularly the RGD-binding integrin subfamily comprising αvβ3, αvβ5, αvβ6, αvβ8, αllbβ3, α5β1, α8β1 and αvβ1 are related to progress and spread of cancer and poor prognosis. Because of the importance of integrin biology in the regulation of cancer dissemination, the integrin receptors are being utilised as targets to regulate cancer progression. The goal of this study was to develop a dual αvβ3/ αIIbβ3 expressing model for testing integrin antagonists. Expression of αv, αIIb, and β3 integrin subunits was characterised using immunofluorescence and flow cytometry in a panel of cell lines. After characterising the expression of αv, αIIb and β3 integrin subunits in inducible and natural expression models (K562 and MCF-7 cells respectively), functional tests for cellular adhesion, detachment and migration were determined. Phorbol 12-myristate 13-acetate (PMA)-treated K562 cells showed increased adhesion on fibrinogen compared to untreated cells. Adhesion of cancer cells (K562 ± PMA and MCF-7) to fibrinogen was inhibited and detachment was induced by the known β3 antagonists, cRGDfV and GR104453. Migration of cancer cells (K562 without PMA and MCF-7) was inhibited by combination of the known β3 antagonists. A panel of 12 novel small molecules developed in the ICT was investigated for cytotoxicity and activity in the validated function assays. ICT9055 was the most potent antagonist in inhibition of cell adhesion, migration, and inducing cell detachment. The data presented in this thesis had selected models and assays for evaluating small molecule integrin antagonists and identified ICT9055 as a promising molecule to develop for further preclinical evaluation.
The Libyan Embassy; Omer Al Mukhtar University, Faculty of Medical Technology, Derna, Libya.
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25

Parks, William. "Force activation of I domain containing and lacking integrins on live cells." Thesis, Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/42695.

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Cellular adhesion plays a crucial role in the biological function of cells, allowing them to communicate and signal, as well as physically anchor, by enabling them to adhere to either other cells or the extra cellular matrix (ECM). This process is regulated by several factors including intrinsic bond kinetics, internal cellular signaling, environment, force exerted on the bond, and force history of the bond. Concerning the force and force history dependence, the observation of catch bonds in integrin binding has asked as more questions than it has answered. To explore the force and force history dependence this process, each bond was loaded to a peak force before relaxing to a much lower force that was held for the duration of the measurement. Two different integrins were studied, both of which have in previous works exhibited a catch bond. Furthermore, the effects of different metal ion conditions and an allosteric antagonist were also studied to elucidate the conformational effects on force priming of integrin. What was observed was that I domain, or αA domain, possessing integrin, whether tested against its more active or less active binding state, changed very little in terms of off rate once the priming force was applied. However in the I domain, or αA domain, lacking integrin, the observed off rate changed as well. It seems that force priming is capable of causing integrin to bind in a stronger manner regardless of the other conditions used to either activate or inhibit binding. However the way in which the binding is strengthened depends on the receptors structure.
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26

Werr, Joachim. "Functions of integrin receptors in extravascular neutrophil migration and respiratory burst /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4337-0/.

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27

Kee, Wai Jing. "Expression and function of the 1B integrin subunit in human keratinocytes." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342261.

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28

Gant, Virgil Alexander. "Detection of integrins using surface enhanced raman spectroscopy." Thesis, Texas A&M University, 2003. http://hdl.handle.net/1969.1/2304.

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Integrins are transmembrane heterodimer protein receptors that mediate adherence to both the intracellular cytoskeleton and extracellular matrix. They play a major role in cellular adhesion and the breadth of their importance in biology is only recently being understood. The ability to detect concentrations of integrins on the cell surface, spatially resolve them, and study the dynamics of their behavior would be a significant advance in this field. Ultimately, the ability to detect dynamic changes of integrins on the surface of a cell maybe possible by developing a combined device such as an atomic force microscope (AFM) and surface enhanced Raman spectroscopy (SERS) system. However, the focus of this research is to first determine if integrins can be detected using SERS. Surface enhanced Raman spectroscopy (SERS) is technique used to detect the presence of analytes at the nanomolar level or below, through detection of inelastically scattered light. This thesis discusses the detection of integrins employing SERS as the detection modality. Integrins have been detected, in solution, using two silver colloids as the enhancing surface. Two silver colloid preparation methods are compared by ease of formulation and degree of enhancement in this thesis. Citrate and hydroxylamine hydrochloride (HA-HCl) reduced silver colloids were prepared through wet chemistry,compared using UV-Vis light spectroscopy, and tested for surface enhancement using adenine (a strong SERS active molecule), and two different integrins, (alpha)V(beta)3 and (alpha)5(beta)1. Results indicated that both colloids demonstrate SERS activity for varying concentrations of adenine as compared to standard non-enhanced Raman, however, only the citrate reduced colloid showed significant enhancement effect for the integrins.
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29

Armulik, Annika. "Studies on the transmembrane signaling of β1 integrins." Doctoral thesis, Uppsala University, Department of Medical Biochemistry and Microbiology, 2000. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1256.

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Integrins are heterodimeric cell surface receptors, composed of an α and a β subunit, mainly binding for extracellular matrix proteins. lntegrin subunit β1 can combine with at least 12 a subunits and thus form the biggest subfamily within the integrin family. In this thesis, functional properties of the splice variant β1Β, and the effects of several mutations in the cytoplasmic tail of integrin subunit β1Α were studied. In addition, the border between the transmembrane and cytoplasmic domains of several integrin subunits was determined.

The β1Β splice variant has been reported to have a dominant negative effect on functions of β1Α integrins. In this study, it was studied if the expression of β1Β had similar negative effects on the αvβ3 integrin functions since the β3 subunit is structurally similar to β1Α. The β1Β subunit was expressed in an integrin β1-deficient cell line and it was found that the presence of β1Β does not interfere with adhesion or signaling of endogenous αvβ3

The border between the cytoplasmic domain and the C-terminal end of the transmembrane domain of integrin α and β subunits has been unclear. This question was experimentally addressed for integrin subunits β1, β2, α2 and α5. It was found that integrin subunits contain a positively charged lysine, which is embedded in the membrane in the absence of interacting proteins.

The functional importance of the lysine in integrin transmembrane domains was investigated by mutating this amino acid to leucine in β1Α. The mutation affected cell spreading and tyrosine phosphorylation of the adapter protein CAS. The activation of focal adhesion kinase and tyrosine phosphorylation of paxillin was not affected. Furthermore, the mutation of two tyrosines to phenylalanines in the β1Α cytoplasmic tail was found to reduce the capability of β1Α integrins to mediate cell spreading and migration. Activation of focal adhesion kinase in response to the later β1Α mutant was shown to be impaired as well as tyrosine phosphorylation of adapter proteins paxillin and tensin whereas overall tyrosine phosphorylation of CAS was unaffected. These data suggests the presence of focal adhesion kinase-dependent and -independent pathways for tyrosine phosphorylation of CAS after integrin β1Α-mediated adhesion.

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30

Sirim, Pinar. "Funktionelle Charakterisierung der Signaltransduktionskaskade des LFA-1-Integrins." Diss., lmu, 2001. http://nbn-resolving.de/urn:nbn:de:bvb:19-3716.

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31

Xie, Xiaojun. "Multiple roles for integrins in Drosophila glial development." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42838.

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Glia are well known for providing essential physical and metabolic support to neurons, as well as regulating neuronal development. Glial development is also modulated by external signals from other cells and the extracellular matrix (ECM). Many signals are transduced into glia by specific receptors, such as integrins for the ECM. Previous studies show that integrins are expressed by all major vertebrate glial subtypes and play key roles in many important developmental processes. However complex composition of the integrin family and difficulties of manipulating genes in vertebrates limit the understanding of in vivo functions of integrins in glia. Drosophila melanogaster is an excellent model for genetic analysis of the nervous system development. In this dissertation, I investigated integrin function in Drosophila glia. Integrins are expressed by glia in both the central and peripheral nervous systems at larval stages, where they form complexes with Talin and Integrin-Linked-Kinase (ILK). I found that integrin complexes were localized to different glia layers in the larval peripheral nerve and optic stalk. By using MARCM and RNA interference techniques, I found that integrins are required for multiple developmental events in individual and populated glia. In the peripheral nerve, integrins are important for glial ensheathment. When integrins were removed, perineurial glia failed to initiate or maintain their wrapping around the nerve and wrapping glia failed to send out numerous membrane processes between axons. In the optic stalk, integrins were necessary for glial migration, deposition and barrier formation. Removal of integrins impaired glial migration into the eye disc. Moreover, perineurial glia tended to aggregate at the anterior half and form multiple layers, and carpet glia failed to form organized septate junctions along the optic stalk. These glial defects resulted in photoreceptor axonal stalling in the eye disc and optic stalk, and mis-targeting in the brain. My work suggests that integrins are important for different aspects of Drosophila glial development and reveals a new glial function in helping photoreceptor axons through the optic stalk. Integrin distribution implicated that integrins may mediate glia-glia or glia-neuron interactions through ECM and non-ECM ligands.
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32

Hyland, Robert H. "Heterodimer formation and activation of the leukocyte integrins." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365411.

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Hutter, Caroline. "Role 1 integrins in epidermal developments and homeostasis." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268448.

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34

Ong, Yen May. "The role of [Beta]1-integrins in centrosomal stability /." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111566.

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Centrosomes are major microtubule organizing centres that set up an internal microtubule (MT) network contributing to cell shape and to the formation of the mitotic spindle during cell division. Rearrangement of this MT array can be dictated by the centrosome and occurs during cell adhesion, polarization and migration. However, little is known about what regulates centrosome assembly and maintenance. beta1-integrins are common cell surface receptors and we show that beta1-integrin signalling is necessary for modulation of centrosome dynamics. In an attempt to identify the downstream components of beta1-integrin signalling involved, we also discovered that the activation of focal adhesion kinase or integrin linked kinase are not required in maintaining centrosome integrity. This would indicate that a non-canonical signalling beta1-integrin pathway might be involved in controlling centrosomal dynamics. This gives us greater insight into the mechanisms that control centrosomal stability and may lead to the better understanding of diseases like cancer and diseases, i.e. lissencephaly, which involve defects in cell polarization and asymmetric cell division, where the centrosome seems to have an important role.
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35

Milner, Richard. "Characterisation of integrins on cells of the oligodendroglial lineage." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360829.

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36

Brunetta, Ivan. "The role of integrins in hair cell precursor differentiation." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/16279/.

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The inner ear sensory epithelium of the organ of Corti is a multicellular structure which detects sound. The inner ear develops from the otic vesicle which contains all the information required for the cells to differentiate and generate all the cell subtypes found in the mature organ of Corti. Organogenesis of the inner ear is a complex process involving different cell functions including cell proliferation and differentiation, all of which are regulated by a network of different factors. Cell adhesion is one of the crucial biological events required by the cells for differentiation. Integrins are the main receptors for adhesion to the extracellular matrix (ECM). The aim of this work was to elucidate the roles of integrins in the differentiation process that occurs in both the organ of Corti and in OC-2 cells; cells that are derived from an immature murine organ of Corti. Immunohistochemistry in mature organ of Corti showed that r31-integrin was expressed in both supporting and hair cells, meanwhile av-integrin was localised mainly in the region of the hair cells. In vitro, αv-, β3-and β1-integrins and the hair cell markers myosin VI and VIIa were expressed at significantly higher levels in differentiated OC-2 cells when compared with undifferentiated OC-2 cells. Furthermore, myosin VI and VIIa were used to monitor the differentiation process occurring in OC-2 cells. siRNA, used to inhibit expression of integrin subunits in differentiated OC-2 cells, was able to decrease the level of expression of myosin VI and VIIa to values comparable with undifferentiated OC-2 cells. Furthermore, the induction of β3-integrin subunit in undifferentiated OC-2 cells was able to increase the expression of myosin VIIa to values comparable with differentiated OC-2 cells, suggesting that this specific integrin subunit possibly is involved directly in the differentiation process in OC-2 cells.
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37

Marshall, John Francis. "The role of integrins in melanoma progression and metastasis." Thesis, Open University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295235.

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38

Hussain, Kiran. "The expression of integrins in the human vestibular system." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10057468/.

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The inner ear is responsible for the detection of sound and movement and therefore subserves hearing and balance. The vestibular system is an integral part of the labyrinth that is housed in the otic capsule of the petrous temporal bone. It is made up of five end organs; the three semiHcircular canals, the utricle and saccule. Mechanoreceptive hair cells, supporting cells and nerve endings make up the sensory neuroepithelia of these organs. Loss of the hair cells in the cochlea leads to deafness and loss in the vestibular system causes balance dysfunction, dizziness and vertigo. Unlike in the cochlea, when this loss occurs in the vestibular system there is in fact a limited capacity for regeneration in mammals. Following hair cell loss induced by ototoxic insult, both in vivo and in vitro, some new hair cells can arise spontaneously. In vivo approximately one third of the hair cells might be replaced with spontaneous reHinnervation. The regenerated new hair cells may be due to the direct phenotypic conversion of supporting cell into hair cells without an intervening mitotic event. Integrins are cell adhesion receptors that play important roles in physiological and pathological processes throughout the body including the vestibular system. The 24 αβ heterodimeric members mediate the interaction of cell - cell transmissions as well as cell H extracellular matrix communication. With specific reference to the vestibular system the role of integrins is potentially integral to the repair and recovery process. The lesion created by the death of a hair cell is closed by supporting cells in a manner that maintains the permeability barrier at the luminal surface of the epithelium. This controlled process relies on cell shape changes and spreading that likely involves integrins. Furthermore, the supporting cells remove these dead hair cells by a phagocytic process. Certain integrins are expressed at the surface of cells that recognise apoptotic cells. Their role in the vestibular system in particular has the potential to provide insight into how disorders of this complex system can be better understood and managed. To date this has not been studied in humans. Explant cultures of vestibular tissue is the only means to perform experimental studies upon the viable human ear. The sensory tissues from the human vestibular system can be obtained from patients undergoing trans labyrinthine procedures for acoustic neuromas. Previous work has shown that they can be maintained ex corporeally in explant culture for periods of up to four weeks. This provides a unique opportunity to study this complex system in humans. This study has identified which integrin subunits are present in the human utricle and localised them. The change in their expression and location following ototoxic injury has also been demonstrated. Crucially, α2, α6, α8, αV, β1 and β5 were located to the basement membrane. α6, αV, β1, β3 β5 and β6 all individually demonstrate interesting patterns and have been implicated in previous work, not just limited to within the inner ear, as playing a potential role in the regenerative processes that occur.
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39

Cimakasky, Lisa M. "The role of integrins in the biology of HIV." Available to US Hopkins community, 2003. http://wwwlib.umi.com/dissertations/dlnow/3080644.

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40

Shaikh, Faheem M. "Role of variant sialylation in regulating tumor cell behavior." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2008d/shaikh.pdf.

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41

Tan, Chin Lik. "Integrin activation in axon regeneration." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609331.

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42

Phan, Isabelle Q. H. "Structural studies of modular proteins by NMR and molecular modelling." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294330.

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43

Andriu, Alexandra. "Evaluating the utility of αvβ3 integrin antagonists to detect and treat angiogenic tumour cells." Thesis, University of Aberdeen, 2018. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=240026.

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Tumour angiogenesis, the formation of new blood vessels within a tumour, is a hallmark of cancers, that allows them to grow beyond a critical size and to metastasize to other organs. As the key driver of tumour angiogenesis, αvβ3 integrin is both an established therapeutic target for anti-angiogenic drugs and a biomarker for imaging agents. Accurate detection of αvβ3 integrin in angiogenic tumours impacts patient prognosis and could report on therapy response. Over the last twenty years, novel αvβ3 integrin-targeted radiotracers have been developed for PET imaging of tumour angiogenesis. While most radiotracers have shown their utility as diagnostic tools, only a few focussed on evaluating response to treatment, partly due to complex biology of the integrin receptors. The aim of this project was the in-vitro biological testing of a novel αvβ3-targeted radiotracer, [3H]ZMPZAT71, and the corresponding unlabelled compound for targeted delivery of a cytotoxic drug, paclitaxel (PTX). Firstly, this piece of work involved validation of this radiotracer to assess expression of αvβ3 integrin. Secondly, [3H]ZMPZAT71 was investigated as a biomarker for assessing response to pharmacological inhibitors of cell signalling pathways. Thirdly, the targeting moiety (ZMPZAT71) conjugated with paclitaxel was studied for integrinmediated drug delivery. The results presented herein demonstrate that radiotracer binding to αvβ3 integrin is dependent not only on the expression levels, but also on the activation status of αvβ3 integrin. Furthermore, this piece of information was used to explain radiotracer binding in response to various pharmacological inhibitors of key cell signalling pathways. Additionally, the integrin-targeted chemotherapeutic exhibited selective cytotoxic effect, explained by enhanced apoptosis of cancer cells compared to PTX alone, together with anti-migratory and anti-invasive effects from the targeting moiety. This study provides valuable information about the molecular mechanisms regulated by αvβ3 integrin, supporting the development of integrin-targeted therapeutics and imaging.
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44

Beranek, Maggi Marie. "The influence of surface integrin binding patterns on specific biomaterial-cell interations [i.e., interactions] a dissertation /." San Antonio : UTHSC, 2008. http://proquest.umi.com.libproxy.uthscsa.edu/pqdweb?did=1588776891&sid=1&Fmt=2&clientId=70986&RQT=309&VName=PQD.

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45

Salvoni, Alexander D'Alvia. ""Análise da expressão de integrinas em células OsA-CL cultivadas sobre implantes de titânio tratado à laser"." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/23/23141/tde-08052006-114723/.

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Diversos estudos têm demonstrado que os implantes de titânio são altamente biocompatíveis e passíveis de osseointegrar, contudo os mecanismos moleculares que atuam por trás da osseointegração permanecem largamente inexplorados. Uma das possibilidades é que o implante exposto ao sangue do paciente durante a cirurgia absorve proteínas relacionadas com a adesão celular, como a fibronectina e vitronectina presentes no plasma. Células como osteoblastos podem então aderir a estas proteínas através dos mecanismos mediadas pelas integrinas. No presente estudo, utilizamos a imunofluorescência para marcação dos anticorpos contra integrinas α2, α3, α5, α6, αv e β1 em células OsA-CL cultivadas sobre lamínulas de vidro e superfície de titânio modificada por radiação à laser no período de 1h à 24 horas. As células aderidas na superfície lisa das lamínulas de vidro tiveram um maior espalhamento durante as primeiras 3 horas, porém nos outros períodos estudados o espalhamento ocorreu de maneira similar em ambas as superfícies. A expressão de integrinas na superfície rugosa dos implantes manteve-se uniforme em todos os períodos estudados, contudo no grupo controle a expressão de integrinas diminuiu na avaliação de 24 horas. Concluiu-se que as características de superfície dos diferentes biomateriais podem afetar o comportamento celular durante a interação inicial das células com a superfície de material utilizado como substrato.
Many studies have been demonstrate that titanium implants are highly biocompatible, however the molecular mechanisms that are behind of the osseointegration process are still largely unexplored. One of the possibilities is that the implant exposed to the patient blood during the surgery, adsorb proteins related to the cellular adhesion. Cells like the osteoblasts can adhere to these proteins trough the mechanisms mediated by integrins. In the present study, we used the immunofluorescence for marking antibodies against α2, α3, α5, α6,, αv and β1 integrins on culture of OsA-CL cells on laminulas of glass and modified titanium surface modified by laser radiation in the period of 1h to 24 hs. Cells adhered in the smooth surface of laminulas of glass had a bigger spreading during the first 3 hours, however in the other studied periods the spreading occurred in a similar way in both surfaces. The expression of integrins in the roughness surface of the implants remained uniform in all the studied periods, but on the control group the integrins expression decreased in the 24-hours evaluation. We concluded that the characteristics of surface of the different biomaterials can affect the cellular behavior during the initial interaction of the cells with the surface of the used material as substratum.
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Gares, Sheryl Lynn. "Thymocyte motility is mediated by ߦ1 integrins and RHAMM." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0009/NQ59590.pdf.

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Thomas, Gareth J. "The role of αv integrins in regulating keratinocyte behaviour." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341916.

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48

Jones, Judith. "The expression and function of integrins in malignant oral epithelium." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309414.

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49

Thomas, Gawain M. "The Role of Integrins in Cellular Response to Mechanical Stimuli." Digital WPI, 2017. https://digitalcommons.wpi.edu/etd-theses/114.

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Tissue cells exhibit varying responses according to the stiffness of their extracellular matrix (ECM). The mechanism of this stiffness sensing is not fully understood; however, it is known that cells probe stiffness by applying intracellular force to the ECM via integrin-mediated focal adhesions. The bonds between integrins and ECM have been described as “catch bonds�, and it is unclear how ECM viscoelasticity affects these bonds. We have observed the effects of ECM stiffness on the binding strength of integrins to ECM ligands by measuring the dissociation force of individual integrin-ligand bonds of 3T3 fibroblasts on collagen-coated polyacrylamide gels using atomic force microscopy. Results show that integrins exhibit higher rates of activation on stiff substrates. Furthermore, increased matrix stiffness results in the occurrence of larger, multi-bond dissociation events, which suggests that substrate stiffness may affect the cellular response by promoting integrin clustering as well as by modulating the maximum possible force between individual integrins and the ECM.
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Wederell, Elizabeth D. "Expression and role of integrins in lens development and cataractogenesis." Thesis, The University of Sydney, 2004. https://hdl.handle.net/2123/27986.

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The mammalian lens is composed of two types of cells enclosed within a thickened basement membrane known as the lens capsule. A monolayer of epithelial cells lines the anterior of the lens while the bulk of the lens is made up of lens fibre cells. After embryonic induction, the lens grows by the proliferation, posterior migration and differentiation of lens epithelial cells in the equatorial region into lens fibre cells. The central epithelium remains relatively quiescent. As fibre cells are formed, they are added to the fibre mass. Here they lose their nuclei and organelles and remain in the lens throughout life, moving filrther into the fibre mass as new cells are added cortically. Abnormal differentiation of lens cells into myofibroblastic/fibroblastic cell-types — an epithelial—mesenchymal transition — results in cataract (anterior subcapsular and posterior capsular opacification). This results in the formation of plaques containing these transformed cells, which express OL—smooth muscle actin, and aberrant matrix proteins, for example collagens I, III, IV, laminin, fibronectin and tenascin. This abnormal transformation can be induced both in vitro and in vivo by TGFB (transforming growth factor B). In lens epithelial explants and whole lens cultures, the addition of TGFB induces the transformation of epithelial cells into myofibroblastic/fibroblastic cell—types. The over-expression of TGFB in lenses of transgenic mice induces the formation of anterior subcapsular plaques which contain not only myofibroblastic/fibroblastic-type cells expressing a—smooth muscle actin, but also fibre-like cells expressing B-crystallin. Both normal and abnormal lens differentiation require dramatic changes in cell morphology, positioning and expression of molecular markers. This requires major changes in expression and activation state of cell adhesion molecules. The integrins are a major family of cells adhesion molecules that play a role in cell-cell and cell—matrix adhesion. They consist of an 0L and a [3 subunit that form a dimer on the plasma membrane and, when active, are linked to specific ligands externally and signalling molecules internally. The Bl group of integrins are mainly involved in cell-matrix adhesion and the mRNA expression of a3, a6 and [31 integrins in the lens was previously studied by this candidate. It was shOWn that the 0L3A subunit was exclusively expressed in the lens epithelium. The (x6B was also expressed in the epithelium and down-regulated in lens fibres while the 0L6A subunit was weakly expressed in the epithelium and up-regulated in lens fibres. The [31 was expressed in both lens epithelium and fibres.
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