Thesis (M.S.)--Bowling Green State University, 2005. / Document formatted into pages; contains viii, 48 p. Includes bibliographical references.

No description available.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

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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No description available.

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.

Thesis (Ph. D.)--Florida State University, 2003. / Advisor: Dr. Kenneth A. Taylor, Florida State University, College of Arts and Sciences, Institute of Molecular Biophysics. Title and description from dissertation home page (viewed 5/4/04). Includes bibliographical references.

Thesis ( Ph.D.) -- University of Texas at Arlington, 2008.

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.