Дисертації з теми "Complement regulators"
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1
Leath, Kirstin J. "Structural Studies of Complement Regulators." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526076.
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2
Chamberlain-Banoub, Jayne L. "Role of complement and complement regulators in peripheral nerve and neuromuscular disorders." Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/55602/.
Повний текст джерелаАнотація:
This thesis describes the evaluation of the role of Complement (C) and C regulators (CRegs) in experimental models of peripheral neuropathy and neuromuscular disease. Although a role for C in mediating peripheral neuropathy has previously been demonstrated in Guillain-Barre Syndrome (GBS) and its well characterised animal model Experimnetal Autoimmune Neuritis (EAN), evaluation of the role of individual components is lacking. C activation has also been widely implicated in the pathology seen in myasthenia gravis (MG) and its associated animal model Experimental Autoimmune Myasthenia Gravis (EAMG), although the precise effectors are uncertain. Evaluation of the extent of protection conferred by CRegs in the peripheral nervous system (PNS), and the ability of the myelin-producing Schwann cell to synthesize C components was a vital first step in determining the susceptibility of the system to C attack, and for providing a method of targeting key C-related molecules for further study in vivo. This work demonstrated that the PNS is well protected from membrane attack complex (MAC) attack, with high expression of the terminal pathway regulator, CD59. Crry was also highly expressed, while CD55 had a limited expression, suggesting a possible alternative role for this protein. CD46 was not expressed in the PNS. Testing the susceptibility of C and CReg deficient and knockout animals to induction of EAN and EAMG would enable further clarification of the role of individual C components to disease pathogenesis. For EAN, various antigens derived from myelin protein zero (PO) were generated to induce disease in rodents. Using this panel of antigens, specific, reproducible EAN was not achieved, and the possible reasons for this are discussed. C activation at the neuromuscular junction (NMJ) contributes to pathology in MG, although the precise role of the MAC is undear. EAMG was used to test the susceptibility of wikHype rats versus rats deficient in the terminal pathway component C6, to disease induction. Wildtype rats demonstrated severe weakness following induction of passively transferred EAMG, while C6 deficient rats were completely protected, demonstrated by protection against clinical disease, reduction in acetylcholine receptor (nAChR) loss, absence of inflammatory infiltrates and lack of C9 deposition. Reconstitution of human C6 to the C6 deficient rats resulted in increased disease. Soluble and fusion protein forms of CRegs, and a novel C5 inhibitor were also tested for their ability to abrogate disease in this model. Preliminary studies of EAMG induction in CReg knockout mice revealed that a lack of CD55 and CD59 markedly enhanced disease, although this remains to be confirmed. In conclusion, this work demonstrates: 1 The potential susceptibility of the PNS to C-mediated pathology 2 The difficulties in inducing EAN in rodents using published protocols 3 That MAC is the major drive to NMJ destruction in EAMG CRegs tested in EAMG hold promise for treatment of inflammatory disease, and analysis of the role of CRegs in EAMG in the mouse may shed new light on the precise effectors mediating disease pathogenesis.
3
McLure, Craig Anthony. "Duplication and polymorphism with particular reference to regulators of complement activation." University of Western Australia. Centre for Molecular Immunology and Instrumentation, 2005. http://theses.library.uwa.edu.au/adt-WU2005.0103.
Повний текст джерелаАнотація:
[Truncated abstract] For the convenience of the reader, detailed figures and tables have been enlarged and compiled in Appendix 2, at the end of this thesis. This thesis is presented as an approach to identify, annotate and detect genomic duplication and polymorphism within large genomic regions. To demonstrate this, I have used as a model, the genomic region known as the Regulators of Complement Activation (RCA). The RCA complex is located on the long arm of chromosome 1 at position 1q32 and is a reservoir of complement regulatory proteins. The genes of the RCA share many similarities implying that all have arisen through multiple complex duplication events. My analysis of this region in the following chapters demonstrates the complexity of this duplication and identifies the many functional units within the RCA. It was my aim at the beginning of these studies to demonstrate an approach that could define the Ancestral Haplotypes (AHs) of the RCA gene cluster. To do this, extensive genomic analysis was required and the ever-increasing availability of genomic sequence has made this thesis possible. Each of the chapters serves to address the following aims set out at the beginning of this thesis: 1. Further characterise the relationship between the genes (Complement Control proteins-CCPs) and domains of the Regulators of Complement Activation (RCA). 2. Identify and examine the duplicated elements within the RCA. - 6 - 3. Examine the effects of retroviruses and other insertions and deletions (indels) in generating the divergence of duplicated genes. 4. Investigate the applicability of the Genomic Matching Technique (GMT) to define AH within the region. 5. Examine association of AHs with CCP implicated diseases. 6. Determine the GMT applicability in non-human species
4
Principato, Silvia, Luca Bini, and Brunella Brunelli. "Investigation of the protective mechanisms mediated by Neisserial Heparin Binding Antigen (NHBA) induced antibodies." Doctoral thesis, Università di Siena, 2021. http://hdl.handle.net/11365/1125830.
Повний текст джерелаАнотація:
Abstract
Neisserial Heparin Binding Antigen (NHBA) is a surface-exposed lipoprotein ubiquitously expressed by Neisseria meningitidis strains and is one of the three main protein components of the Bexsero vaccine. NHBA binds heparin and heparan sulfates through an arginine-rich region and is cleaved by meningococcal and human proteases. Its expression is upregulated at 32°C [1] and it is sparsely distributed on the bacterial surface. Additionally, recent evidence suggests that NHBA plays a key role in bacterial adherence through its arginine-rich region [2].
NHBA induces bactericidal antibodies in humans and confers protective immunity in the infant rat animal model. Anti-NHBA antibodies (polyclonal and monoclonal) from mice and humans are functional, being able to induce complement-mediated bacterial killing, in the presence of rabbit complement (rSBA). However bactericidal activity is not measurable when human serum is used as the source of complement (hSBA).
The aim of this investigation was to elucidate the functional properties that determine the mechanisms of protection mediated by anti-NHBA antibodies.
Negative regulators of the complement system, such as factor H and vitronectin, have been investigated. The effects of antigen density have been explored using a genetically engineered NHBA overexpressing strain to characterize a panel of anti-NHBA monoclonal antibodies isolated from Bexsero immunized adults [3]. Monoclonal antibodies with enhanced C1q recruitment ability have been used to investigate the effect of antigen density and distribution. Moreover, the infant rat challenge model has been used to evaluate in vivo anti-NHBA antibodies induced passive protection.
Nonspecific downregulation of complement-mediated killing due to human factor H was observed to cause an underestimation of the anti-NHBA antibodies ability to efficiently kill bacteria in hSBA, despite the strong passive protection observed in the in vivo infection model. An interaction of NHBA with the complement down-regulator vitronectin was also demonstrated. By using a genetically engineered NHBA overexpressing strain, the relevance of antigen density on the bactericidal activity of antibodies was highlighted. A reduced antigen density on the bacterial surface was shown to be overcome by using engineered monoclonal antibodies with enhanced C1q recruitment ability.
It was demonstrated that multiple interactions with complement regulators interfere with the in vitro measurement of the bactericidal activity mediated by anti-NHBA antibodies in the presence of human complement. Interestingly NHBA, as the Neisseria Opc and NhhA, was found to interact with the extracellular matrix component vitronectin, opening the way to future studies to elucidate implications of this interaction for bacterial colonization. Taken together our findings further support the important role played by NHBA in meningococcal pathogenesis and immunity.
References
[1] M. Lappann et al., Impact of moderate temperature changes on Neisseria meningitidis adhesive phenotypes and proteome. Infection and immunity, 18, 3484-3495, 2016.
[2] I. Vacca et al., Neisserial heparin binding antigen (NHBA) contributes to the adhesion of Neisseria meningitidis to human epithelial cells. PloS One, 11, e0162878, 2016.
[3] M. Giuliani et al., Human protective response induced by meningococcus B vaccine is mediated by the synergy of multiple bactericidal epitopes. Scientific Reports, 8, 3700, 2018.
Disclosures
This work was sponsored by GlaxoSmithKline Biologicals SA.
Silvia Principato is a student of the University of Siena (Life Science Department) and participates in a PhD program at GSK. At present, SP is an employee of the GSK group of companies.
Bexsero is a trademark of the GSK group of companies.
Human monoclonal Antibodies were obtained from adults in a Phase I clinical study conducted in Krakow, Poland and sponsored by Novartis Vaccine, now part of the GSK group of Companies, using two doses of multicomponent serogroup B meningococcal vaccines. The Clinical trial protocol was approved by the Bioethics Committee of the District Medical Doctors’ Chamber in Krakow and the study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from each of the subjects.
All animal studies were ethically reviewed and carried out in accordance with European Directive 2010/63/EEC and the GSK policy on the Care, Welfare and Treatment of Animals.
5
Demberg, Thorsten. "Analyse und Expression der Komplementproteine Faktor H und Faktor I der Ratte." Doctoral thesis, [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=970362927.
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6
Piccoli, Amanda Kirchner. "Expressão de proteínas reguladoras do complemento CD55/CD59/CD35/CD46 em pacientes com artrite reumatóide." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2011. http://hdl.handle.net/10183/28210.
Повний текст джерелаАнотація:
A Artrite Reumatóide (AR) é uma doença autoimune associada a poliartropatia inflamatória que acomete principalmente as articulações periféricas. Cerca de 1% da população mundial é afetada, sendo duas a três vezes mais prevalente em mulheres. Apresenta uma patogênese complexa e multifatorial. A sinóvia das articulações afetadas é infiltrada por linfócitos T e B, macrófagos e granulócitos. A sinóvia reumatóide adquire características proliferativas, formando o pannus, e invade a cartilagem articular e o osso, levando à destruição da arquitetura normal da articulação e perda de função. Em vários modelos de doenças autoimunes, a ausência ou diminuição da expressão de proteínas reguladoras do complemento tem sido observada, associada com o agravamento dos sintomas clínicos, sendo que, muitos destes casos, a superativação do sistema complemento pode ser a causa da exacerbação da doença. O presente artigo tem por objetivo revisar os principais aspectos relacionados à regulação do sistema complemento na artrite reumatóide, a fim de propiciar uma melhor compreensão do potencial papel desse sistema na fisiopatologia da doença.Rheumatoid arthritis (RA) is an autoimmune disease associated with polyarticular inflammatory synovitis that affects mainly the peripheral joints. About 1% of the world population is affected, and it is two to three times more prevalent in women. RA has a complex and multifactorial pathogenesis. The rheumatoid synovium acquires proliferative characteristics, forming the pannus, and invades cartilage and bone, leading to the destruction of normal architecture and loss of function. In several models of autoimmune diseases, the absence or decreased expression of complement regulatory proteins has been observed, associated with worsening of the clinical symptoms, and many of these cases the over-activation of the complement system is the cause of disease exacerbation. This article aims to review the main aspects related to regulation of the complement system in rheumatoid arthritis in order to provide a better understanding of the potential role of this system in the pathophysiology of the disease.
7
Soames, Candida J. "Factor H : a major complement regulatory protein." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307011.
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8
Pasch, Marcel Christian. "Regulation of expression of complement components, complement regulatory proteins, and chemokines in keratinocytes." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2000. http://dare.uva.nl/document/56902.
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9
Lewis, Ruth D. "The role of complement and complement regulatory proteins in the progression of atherosclerosis." Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/54224/.
Повний текст джерелаАнотація:
Whilst evidence from human studies suggests that complement activation is pro-atherogenic, studies using animals models of the disease, including the low density receptor deficient (ldlr
10
Chen, Jin. "Role of Complement Regulatory Protein Properdin in Hemolytic Anemias Caused by Complement Dysregulation." University of Toledo Health Science Campus / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=mco1576192779405742.
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11
Lin, Lin. "Complement-Related Regulates Autophagy in Neighboring Cells." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/911.
Повний текст джерелаАнотація:
Autophagy is a conserved process that cells use to degrade their own cytoplasmic components by delivery to lysosomes. Autophagy ensures intracellular quality control and is associated with diseases such as cancer and immune disorders. The process of autophagy is controlled by core autophagy (Atg) genes that are conserved from yeast to mammal. Most Atg proteins and their regulators were identified through pioneering studies of the single cell yeast Saccharomyces cerevisiae, and little is known about factors that systematically coordinate autophagy within the tissues of multicellular animals. The goal of this thesis is to identify new autophagy regulators and provide a better understanding of the regulatory mechanisms within multicellular animals. My research determined Macroglobulin complement-related (Mcr), a Drosophila complement orthologue, can activate autophagy during developmental cell death. Unlike most known autophagy regulators, Mcr functions in a cell non-autonomous manner to trigger autophagy in neighboring cells. To my knowledge, this is the first identified autophagy factor that cell non-autonomously activates autophagy. Additionally, I found that Mcr, a secreted protein, instructs the autophagy machinery through the immune receptor Draper, suggesting a relationship between autophagy and the control of inflammation. Lastly, Mcr is dispensable for both nutrient deprivation-induced autophagy in the fat body and developmentally programmed autophagy in the dying midgut of Drosophila. Therefore, this study unveils a mechanism in a multicellular organism by which autophagy is systematically controlled in distinct cell contexts.
12
Lin, Lin. "Complement-Related Regulates Autophagy in Neighboring Cells." eScholarship@UMMS, 2006. http://escholarship.umassmed.edu/gsbs_diss/911.
Повний текст джерелаАнотація:
Autophagy is a conserved process that cells use to degrade their own cytoplasmic components by delivery to lysosomes. Autophagy ensures intracellular quality control and is associated with diseases such as cancer and immune disorders. The process of autophagy is controlled by core autophagy (Atg) genes that are conserved from yeast to mammal. Most Atg proteins and their regulators were identified through pioneering studies of the single cell yeast Saccharomyces cerevisiae, and little is known about factors that systematically coordinate autophagy within the tissues of multicellular animals. The goal of this thesis is to identify new autophagy regulators and provide a better understanding of the regulatory mechanisms within multicellular animals. My research determined Macroglobulin complement-related (Mcr), a Drosophila complement orthologue, can activate autophagy during developmental cell death. Unlike most known autophagy regulators, Mcr functions in a cell non-autonomous manner to trigger autophagy in neighboring cells. To my knowledge, this is the first identified autophagy factor that cell non-autonomously activates autophagy. Additionally, I found that Mcr, a secreted protein, instructs the autophagy machinery through the immune receptor Draper, suggesting a relationship between autophagy and the control of inflammation. Lastly, Mcr is dispensable for both nutrient deprivation-induced autophagy in the fat body and developmentally programmed autophagy in the dying midgut of Drosophila. Therefore, this study unveils a mechanism in a multicellular organism by which autophagy is systematically controlled in distinct cell contexts.
13
Strainic, Michael George Jr. "THE ABSENCE OF C3AR AND C5AR SIGNAL TRANSDUCTION PROMOTES T REGULATORY CELL DIFFERENTIATION AND REGULATES IMMUNOLOGIC TOLERANCE." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1363707372.
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14
Bradley, Richard Grayson. "Development of cancer immunotherapeutics targeting complement regulatory protein CD55." Thesis, University of Nottingham, 2007. http://eprints.nottingham.ac.uk/10258/.
Повний текст джерелаАнотація:
CD55 is one of the complement regulatory/inhibitory proteins and is over-expressed on a wide range of solid tumours. CD55 is also known to be deposited within tumour stroma and is secreted in an active soluble form, mediated by matrix metalloproteinase-7. The complement cascade forms part of the innate immune system and culminates in cell lysis of targeted cells. As a complement regulatory protein, the primary function of CD55 is to accelerate the decay of complement components preventing formation of the membrane attack complex. CD55 is also known to be a ligand for the T cell early activation antigen CD97, and their interaction has been shown to inhibit the proliferation of activated T cells. This project aimed to develop anti-tumour immunotherapeutics aimed at exploiting CD55 as a tumour associated antigen. Initial strategies were to develop monoclonal antibodies, specific to identified epitopes from within the CD55 protein sequence, capable of binding, and neutralising CD55s decay accelerating activity. Developed antibodies would also have the potential to induce antibody dependent cell cytotoxicity, thus blocking CD55 protection of tumours and mediating an active anti-tumour response. Antibodies were raised specific to CD55 derived linear peptides, which have been used for the assessment of CD55 expression in breast tumour sections. Monoclonal antibodies failed to recognise natively expressed protein on viable tumour cells and alternate strategies were developed. An effective immunotherapy for the treatment of cancer would engage both cellular and humoral mediated responses for effective clearance of target cells. In order to achieve this, a DNA vaccine incorporating a human IgG Fc tail was developed expressing the active sites of CD55, containing HLA-A*201 restricted heteroclitic epitopes. The vaccines were used to immunise HLA-A*201 HHDII transgenic mice and CD55 specific responses were assessed. One of the vaccines analysed, elicited CD55 specific antibodies capable of recognising tumour cells in vitro and also generated epitope specific CD8+ T cell mediated lysis of epitope bearing cells. The frequency of CD55 specific T cells was obtained via antigen specific IFN gamma release ELISPOT assays and the cytokine profile of responses generated was assessed via luminex analysis. In conclusion, CD55 remains a viable target for immunotherapies aimed at CD55 bearing tumours. DNA vaccines encoding modified epitopes are capable or raising cellular and humoral responses to this antigen and further studies should be completed in order to determine anti-cancer effects in tumour bearing models.
15
Hovis, Kelley M. "The Relapsing Fever Spirochete, Borrelia Hermsii, and Complement Regulatory Proteins." Available to VCU users online at:, 2007. http://hdl.handle.net/10156/1892.
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Simpson, Karen Lesley. "Expression of complement regulatory proteins in human development and reproduction." Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294904.
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17
El, Feki Shereen Gwen. "CR1-CD59 chimera : a novel recombinant regulator of complement activation." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627074.
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Hepburn, Natalie Jayne. "Recombinant rat complement regulatory proteins as therapeutic agents in inflammatory disease." Thesis, Cardiff University, 2006. http://orca.cf.ac.uk/56102/.
Повний текст джерелаАнотація:
The complement system has become a therapeutic target due to its involvement in a number of inflammatory conditions. Soluble recombinant forms of the membrane- associated regulators (CReg) have been created as therapeutics. However, these reagents are limited by their short half-lives in vivo and their tendency to systemically inhibit complement. To extend their circulating half-lives Fc fusion proteins have been generated while targeting reagents to sites of inflammation or inhibiting specific parts of complement, such as the terminal pathway, has been used to overcome systemic complement inhibition. Many of the reagents generated to date are based upon human proteins and are therefore immunogenic in rats, preventing their testing in rat models of chronic disease. To enable the testing of anti-complement therapeutics in rat models of chronic disease, various CReg-Fc containing a rat Fc and different portions of rat Crry were generated in this study. Functional analysis of the generated reagents was carried out to identify two different Crry-Fc. One would retain full activity while the other would address the issues of systemic complement inhibition by having negligible activity in the circulation, due to steric hindrance imparted on the Crry by the Fc, but could be cleaved at inflammatory sites to unleash an active regulator. A Crry-Fc that retained full activity was identified and tested in vivo. This reagent had a long circulating half- life, low immunogenicity and markedly reduced disease severity in a rat model of myasthenia gravis. Attempts to generate a Crry-Fc that had negligible activity in the circulation but could be cleaved at inflammatory sites to unleash anti-complement activity were unsuccessful. The generation of the active Crry-Fc reagent paves the way to testing anti-complement therapeutics in rat models of chronic disease.
19
Saggu, Gurpanna. "Role of Complement Regulatory Protein Properdin in Complement Activation on Platelets and in the Formation of Platelet-Leukocyte Aggregates." University of Toledo Health Science Campus / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=mco1392998532.
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Pickel, Donnie. "Investigating Complement Regulator Involvement in Innate Immune Evasion by Neisseria gonorrhoeae." Ohio University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1628181973757983.
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Fett, Anna Laura [Verfasser]. "Immunohistochemical localization of complement regulatory proteins in the human retina / Anna Laura Fett." Köln : Deutsche Zentralbibliothek für Medizin, 2012. http://d-nb.info/1030599955/34.
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22
Madjid, Zahra. "Expression of complement regulatory proteins and MHC class 1 molecules on breast carcinomas." Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415624.
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23
Alwashmi, Ameen Salem Suliman. "The regulatory activities of recombinant properdin and TSP1 on platelet and complement activation." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/40955.
Повний текст джерелаАнотація:
The complement system provides a first line defence against microbial pathogens and cooperates with platelet activation of haemostasis/thrombosis system in a physiologically meaningful way by forming a physiological barrier to prevent blood loss following vascular injury. Due to chondroitin sulphate (CS) secretion from activated platelets, some pattern recognition molecules, i.e. MBL, CL-11 and ficolins of the lectin pathway (LP), and C1q of the classical pathway (CP) can drive complement activation on the surface of activated platelets. Properdin is, a positive regulator of the AP, is entirely composed of thrombospondin-like domains (TSR) sharing a high degree of identity with TSR Type-I repeat of Thrombospondin-1 (TSP1). TSP1 is an adhesive homo-trimeric glycoprotein that is re-leased during platelet activation. The structural similarities between properdin and TSP1 are striking. The current result showed a highly significant difference of P-selectin expression level which was observed in washed activated human platelets triggered by 10μg/ml (w/v) of highly oligomerised properdin using ELISA in comparison with other known agonists, including TSP1. Platelet activation resulted in α-thrombin release as shown by ELISA as well as thrombin generation monitored using platelet microparticles (PMPs). My work demonstrated for the first time that highly oligomerised properdin can bind to in-tact platelets while the binding of the physiologically occurring lower grade properdin oligomers; i.e. dimers, trimers and tetramers, to resting platelets was not observed. These lower grade oligomers only bind to activated platelets. That demonstrated the ca-pability of highly oligomerised properdin to promote platelet adhesion. The activation was suggested through binding directly to platelet receptors or indirectly through sup-porting extracellular matrix (ECM) in sub-endothelial layer. The binding was observed with Collagen Type-I, von Willebrand factor (vWF) and Fibronectin (Fn), also, with atherogenic particles such as Low-density lipoprotein (LDL), cholesterol and triglycerides. The crosstalk between activated platelets and the complement system was investigated by screening for a possible regulatory role of TSP1 during complement activation. 10μg/ml (w/v) of TSP1 were found to significantly down-regulate complement activation using C3 and C4 deposition assays under alternative pathway or lectin pathway specific assay conditions. While the down-regulation of lectin pathway functional activity was due to direct TSP1 binding to mannan and Chondroitin sulphate (CS) on the activator surface competing for the binding of MBL and/or CL-11, TSP1 was shown to inhibit the alternative pathway through direct binding to factor B (fB) and/or to C3 with surprisingly high binding affinity. TSP1 binding led to a competitive inhibition of properdin functional activity. These results suggest that TSP1 acts as a negative regulator which significantly shortens the half-life of the C3 and C5 convertase complexes of the AP. Therefore, native TSP1 may act as a negative fluid-phase regulatory component of complement activation to protect activated-platelets from overshooting complement activation. TSP1 is believed to influence the colonisation and dissemination of microbial pathogens such as Streptococcus pneumoniae. My results demonstrate that TSP1 release may in part protect S.pneumoniae (D39) from complement mediated killing, as demonstrated in a serum bactericidal assay (SBA). That may suggest that for colonisation/dissemination, TSP1 may help the pathogen to escape from elimination by the complement system. In conclusion, my results propose a so far unknown physiological role of TSP1 as a negative regulator of the alternative pathway activation route of complement by shorting the half-life of the LP and/or AP C3 and C5 convertases and as such may provide a new example of synergisms and antagonisms between the platelet and the complement system.
24
Basmarke-Wehelie, Rahma, Hong Sjölinder, Wiktor Jurkowski, Arne Elofsson, Anna Arnqvist, Lars Engstrand, Matthias Hagner, et al. "The complement regulator CD46 is bactericidal to Helicobacter pylori and blocks urease activity." Stockholms universitet, Institutionen för genetik, mikrobiologi och toxikologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-63669.
Повний текст джерелаАнотація:
BACKGROUND & AIMS: CD46 is a C3b/C4b binding complement regulator and a receptor for several human pathogens. We examined the interaction between CD46 and Helicobacter pylori (a bacterium that colonizes the human gastric mucosa and causes gastritis), peptic ulcers, and cancer. METHODS: Using gastric epithelial cells, we analyzed a set of H pylori strains and mutants for their ability to interact with CD46 and/or influence CD46 expression. Bacterial interaction with full-length CD46 and small CD46 peptides was evaluated by flow cytometry, fluorescence microscopy, enzyme-linked immunosorbent assay, and bacterial survival analyses. RESULTS: H pylori infection caused shedding of CD46 into the extracellular environment. A soluble form of CD46 bound to H pylori and inhibited growth, in a dose- and time-dependent manner, by interacting with urease and alkyl hydroperoxide reductase, which are essential bacterial pathogenicity-associated factors. Binding of CD46 or CD46-derived synthetic peptides blocked the urease activity and ability of bacteria to survive in acidic environments. Oral administration of one CD46 peptide eradicated H pylori from infected mice. CONCLUSIONS: CD46 is an antimicrobial agent that can eradicate H pylori. CD46 peptides might be developed to treat H pylori infection.
25
Rolland, Philip. "The expression of HLA class I molecules and complement regulatory proteins in ovarian cancer." Thesis, University of Nottingham, 2008. http://eprints.nottingham.ac.uk/10600/.
Повний текст джерелаАнотація:
Over recent decades, translational ovarian cancer research has been impeded by its underappreciated molecular heterogeneity and five-year survival has remained poor. One strategy for addressing this problem is to search for molecular biomarkers that can better inform the development and targeting of novel treatments. The aim of this thesis was to construct and validate a tissue microarray of ovarian cancer cases and to survey the expression and prognostic capabilities of immunological molecular markers: specifically HLA class I and the membrane bound complement regulatory proteins CD46, CD55 and CD59. These are central to the efficacy of certain immunotherapies and while they have been shown to have prognostic power in breast and colorectal cancer, they have been investigated less in ovarian cancer. Five copies of a tissue microarray representing 339 cases of ovarian cancer which presented to Derby City General Hospital between 1982 and 1997 were made. The array was stained for CK7, CK20, CA125, CEA, p53 and Bcl-2 following a standard immunohistochemical protocol. A linked clinical database was adapted and assessed for data consistency and subsequently used to analyse the prognostic and clinicopathological associations of the expression data. The array was then stained for HLA class I, B2microglobulin and CD59 using commercial antibodies and for CD55 and CD46 using in-house antibodies. Retained expression of HLA class I molecules independently predicted improved prognosis. High expression of CD55 and CD59 were associated with worse prognosis, though not independently of other factors. CD55 expression was more widespread than previously appreciated. This thesis describes the discovery of a new independent marker of prognosis which suggests that immunoediting occurs in ovarian cancer, describes the distribution of markers known to have a negative impact on immunotherapy in ovarian cancer in a large series for the first time and documents the production of a valuable resource for future studies.
26
Blatt, Adam Z. "Role of Complement Regulatory Proteins Properdin and Factor H in Platelet/Granulocyte Aggregate Formation." University of Toledo Health Science Campus / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=mco1466860499.
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Ahmad, Saifur Rehman. "The regulation and function of the complement regulatory protein decay-accelerating factor on murine endothelium." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405432.
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Tsang, Patricia Siu-Yee. "An active role of complement regulatory proteins in the development of the epithelial response to infection." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.429269.
Повний текст джерела
29
Lindström, Nils. "Prokaryotic expression of human complement regulator factor H domains and their interaction withPneumococcal surface protein PspC." Thesis, KTH, Skolan för bioteknologi (BIO), 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-215297.
Повний текст джерелаАнотація:
One of the oldest and most exciting questions in science is: are we alone in the universe? During the last four billion years of Earth’s history, countless organisms have inhabited almost every environmental niche on the planet, from the deepest sea to driest deserts. However, so far no extraterrestrial life has been found. Studying the propensity for life on our neighboring planet, Mars,helps us understanding its potential for past and present life, and guides future missions. Liquid water is a prerequisite for life as we know it and recently, evidence of transient night time liquidbrines on the surface of present day Mars have been theorized. These brines may be hyper-salinewith high ionic strengths and varying pH-values. Halobacterium salinarum is an extremophilic (saltloving) halophilic archaeon whose natural habitat includes hyper-saline brines, desiccating conditions and exposure to high fluences of solar UV radiation. Herein, we report the response of Hbt.salinarum following exposure to simulated Martian conditions, with regard to survival and DNAintegrity. The simulated conditions include the synthetic Martian Brine Analogues (MBAs), diurnalnocturnaltemperature cycling, prolonged desiccation and Mars-like solar UV (200-400 nm) radiation.We also addressed the prolific space hardware contaminant, Bacillus subtilis whose endospores show substantial resistance against space conditions. The ambition was to investigate potentia linterplanetary forward contamination by Hbt. salinarum, should it have bacterial spores available as nutrients in the Martian brines. Halophiles are some of our best candidates for studying unicellular life on Mars and other bodies where liquid water is also stabilized by high salt concentrations.Moreover, Hbt. salinarum was able to survive over one month in the Martian brines, albeit with growth limited to one particularly hospitable brine. It displayed survival in the brines at relevant temperatures and with diurnal-nocturnal cycling but only when first desiccated to remove preventwater crystal formation. The radiation resistance was highly dependent on the choice of brine inwhich Hbt. salinarum was confined and desiccated. Even in the hospitable brines, the halophile lost over 90% of its viable population following irradiation equal to one Martian day, in our experimentalsetup. The inter-brine difference in DNA fragmentation following irradiation confirmed the differencein survival. Hbt. salinarum was subsequently unable to digest B. subtilis endospores for nutrient exploit and responded no differently than when nutrient-deprived. Surprisingly, the addition of otherwise available nutrients in the brines caused a hurried decrease in survival, with the exception of the hospitable brine. Despite its extremophilic and polyextremotolerant character, Hbt. salinarumis unlikely to survive, not to mention thrive, in a combination of all tested stressors.
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Ocariza, Linnette Mae. "Polyphosphate : a novel negative regulator of complement and its therapeutic potential in age-related macular degeneration." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/55196.
Повний текст джерелаАнотація:
The innate mammalian response to injury involves the initiation of activation of two major blood-borne proteolytic systems; coagulation and complement. Recent studies have revealed that there is considerable crosstalk and interplay between these two systems. Polyphosphate (polyP) is a naturally occurring inorganic linear polymer that co-regulates these two systems, acting as a promoter of coagulation and an inhibitor of complement. This thesis aims to further characterize the mechanisms by which polyP regulates the complement system, and to test its physiological relevance in a model of human disease, age-related macular degeneration (AMD), the pathogenesis of which involves excess complement activation and oxidative stress. Based on data from our lab and studies in bacteria that polyP dampens complement activation and interferes with oxidative stress, I hypothesized that polyP would protect against AMD. To test this hypothesis, I used hemolytic assays to measure the complement activity in response to polyP, in vitro studies with AMD-associated cell lines to examine protective properties of polyP, and an in vivo model of AMD to evaluate the therapeutic efficacy of polyP. I showed that polyP dampens complement activation by interfering with the terminal pathway of complement, and that it also interferes with oxidative stress-induced cellular damage. The mechanisms by which it exerts this effect have not yet been determined. However, in vivo, in rodent models of AMD, polyP protects against laser-induced choroidal neovascularization (CNV), a feature of AMD, with reduced deposition of complement. An agent such as polyP, that simultaneously suppresses complement activation and protects against oxidative stress, holds potential therapeutic value. The findings in this thesis raise awareness of the potential importance of a ubiquitous, naturally occurring inorganic compound that has largely been overlooked. Most important, the findings reveal a promising use for polyP as a treatment for AMD, a common and devastating disease that affects millions of people worldwide.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
31
Ren, Zhaozhou [Verfasser]. "The role of complement component C6 and the MAC-regulator CD59a in skeletal homeostasis / Zhaozhou Ren." Ulm : Universität Ulm, 2019. http://d-nb.info/1188321102/34.
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Pechtl, Isabell C. "Study of complement regulatory factor H based on Forster resonance energy transfer and investigation of disease-linked genetic variants." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4721.
Повний текст джерелаАнотація:
The plasma protein complement factor H (fH, 155 kDa) regulates the activity of the alternative pathway of complement activation. Factor H is monomeric, and its 20 CCP modules are arranged in a predominantly elongated conformation, joined by linking sequences that vary in length, with the longest linkers occurring in the central portion of the molecule. CCP modules 1 through 4 of fH host its capacity to act as a cofactor for fI-mediated proteolytic degradation of C3b and its ability to accelerate the decay of the C3 convertase, C3bBb, thereby regulating the so-called tick-over activation of the alternative pathway. Mutations in this part of fH might compromise its function and lead to underregulation of the alternative pathway. It is hypothesized that this can cause predisposition to diseases such as atypical haemolytic uraemic syndrome (aHUS) and age-related macular degeneration (AMD). In the current work, the known disease-associated mutations R53H and R78G were compared to wild-type in terms of fluid-phase cofactor assays, C3b-binding affinity and the ability to accelerate the decay of the convertase. In addition, the protective variant, I62, was also inspected because its protective role might be explained by an increased regulatory activity. The second, linked, aim of this project was to employ Forster resonance energy transfer (FRET) to study the link between conformation and function in fH. FRET is valuable for obtaining long-distance restraints up to a maximum of 100 °A and is therefore particularly useful for inferring domain orientations within multidomain proteins. This approach to measure long-range inter- and intramolecular distances is a convenient way to complement NMR-based structural investigations, which rely on short-range restraints. It is also a valuable complement to X-ray crystallography since it is a solution technique that can be conducted under physiological conditions. By using site-directed mutagenesis in the current work, free cysteines were introduced into CCP modules 1-4 at strategic points, which were then used for attachment of fluorescent tags. C3 possesses an internal thioester which can be labelled with a fluorophore upon activation to C3b. Intermolecular FRET measurements were thus undertaken to gain information about the interaction between the two proteins that is crucial for understanding functional activity. The CCP modules in the centre of fH may be responsible for introducing a bend into fH that brings the N-teminus close to the C-terminus (the latter is important for host versus non-host discrimination) joined by the longest linkers occurring in the whole molecule. This coincidence of two relatively small CCP modules, 12 and 13, with the highest number of eight amino acids between them, is hypothesised to reflect some unique architectural features. To explore the structural details of this portion of fH by FRET, single-labelled cysteine mutants were further modifed to provide a recognition site for transglutaminase (TGase), which can be enzymatically labeled with a second fluorophore. This stoichiometrically-labelled protein was used for intramolecular FRET studies.
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Pollard, Alison Jane. "Characterisation of CD46 isoforms in human peripheral blood cells : localisation of complement regulatory proteins throughout the male reproductive tract." Thesis, University of Liverpool, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365911.
Повний текст джерела
34
Slingsby, Fern. "Investigating a C1QTNF5 mutation associated with macular degeneration." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4220.
Повний текст джерелаАнотація:
C1QTNF5 is a 25kDa short chain collagen of unknown function which is mutated in late-onset retinal macular degeneration (L-ORMD). L-ORMD is an autosomal dominant disease characterised by sub-retinal pigment epithelial deposits leading to photoreceptor death and visual loss and shows several similarities to age-related macular degeneration (AMD). A Tyr402His polymorphism in complement factor H (CFH), a regulatory protein in the innate immune system, has been associated with increased risk of AMD. C1QTNF5 and CFH are both expressed and secreted by the retinal pigment epithelium (RPE) which supports photoreceptors and is responsible for phagocytosis of shed rod photoreceptor outer segments (ROS). The properties of the normal C1QTNF5 and disease-associated Ser163Arg mutation were examined in detail, including protein characterisation, cellular processing and function. Recombinant wild type and mutant C1QTNF5 were produced and their multimerisation and solubility functions compared. Both proteins were found to be soluble and to form similar multimeric species which were resistant to reducing conditions, as seen in other short chain collagens. Due to the similarities between LORMD and AMD, a proposed interaction between C1QTNF5 and CFH was investigated. CFH is composed of 20 short consensus repeats (SCR) and interactions were confirmed between C1QTNF5 and both CFH and SCR modules 7-8 and 19-20. CFH showed a greater affinity for mutant C1QTNF5 compared with wild type on the basis of surface plasmon resonance assays. Stably transfected RPE-derived cell lines were created which expressed either wild type or mutant C1QTNF5. Both proteins were found to be secreted and showed similar cellular processing with no evidence of aggregation or retention of the mutant protein within the endoplasmic reticulum. In order to investigate C1QTNF5 function, phagocytosis of ROS by the stably transfected cell lines was carried out. Cells expressing wild type C1QTNF5 showed greater ROS phagocytosis compared with mutant C1QTNF5-expressing or untransfected cells. Addition of anti-C1QTNF5 antibody increased ROS phagocytosis further. In summary, it is proposed that wild type and mutant C1QTNF5 are secreted by the RPE where they interact with CFH. C1QTNF5 is also shown to have a role in ROS phagocytosis, with mutation in C1QTNF5 affecting phagocytosis efficiency, which may contribute to sub-RPE deposit formation. The results suggest that CFH may also be involved in this process, suggesting a common pathogenic pathway between L-ORMD and AMD.
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Gomes, Pereira Neuza Alexandra. "Cloning and expression of a functionally active truncated N-glycosylated KSHV complement regulatory protein and immunohistochemical studies with the anti-KCP peptide antibody." Master's thesis, University of Cape Town, 2005. http://hdl.handle.net/11427/25664.
Повний текст джерелаАнотація:
Kaposi sarcoma herpes virus (KSHV) is a typical DNA virus that is associated with a number of proliferative diseases including Kaposi's sarcoma. The KSHV open reading frame (ORF) 4 encodes a complement regulatory protein (Kaposi complement-binding protein, KCP) that binds complement proteins and inhibits the complement-mediated lysis of cells infected by the virus, thus providing a strategy for evasion of the host complement system. Kaposi's sarcoma is an angiogenic skin lesion that has been recognized as one of the most abundant tumours found in many parts of Southern Africa and which can occasionally become highly invasive, aggressive and capable of causing death, particularly amongst AIDS patients. It is of major significance to understand how complement control proteins (CCPs) such as KCP perform their biological functions at the molecular and structural levels, because of their potentials as therapeutic agents, their implications in the pathology and importance in the etiology of many disease conditions. This study was therefore undertaken to characterise the structure-function relationship of KCP. Based on primary sequence analysis and comparison to other functionally and structurally similar proteins, oligonucleotide primers were designed to amplify by PCR, three regions of the predicted ORF 4 from human herpes virus-8 (llliV-8) DNA isolated from a primary effusion lymphoma cell line. The PCR products were inserted by ligation into the expression vector pPIC9 to generate three recombinant plasmids for heterologous expression in the yeast, Pichia pastoris and to produce separately, the 4 N-terminal Sushi domains (KCP-S, small), KCP protein lacking the putative transmembrane binding domain (KCP-M, medium) and the full-length protein (KCPF, full). Expression of the viral proteins was confirmed by SDS-PAGE and Western blot analyses using a rabbit polyclonal antibody directed against a selected peptide region that is common to all three recombinant KCPs. All the KCP proteins migrated electrophoretically as higher bands compared to their expected sizes. The lower mobilities of the proteins may be due to g1ycosy1ation since there are potential N-and O-glycosylation sites in the protein's primary sequence. Also, diffused bands were obtained in all the electrophoretic gels and Western blots carried out, which is characteristic of glycoproteins. Furthermore, the antibody recognized several larger and smaller bands that may represent aggregates and/or degradation products respectively. Both partially purified KCP-S and KCP-S directly from expression media were able to inhibit complement-mediated lysis of sensitized sheep erythrocytes by approximately 60% in a hemolysis assay. This result confirms previous reports that recombinant KCP is twice more efficient in inhibiting the classical pathway-mediated lysis of erythrocytes than the vaccinia virus complement control protein (VCP), which also contains 4 Sushi domains. The KCP-F and KCP-M proteins did not show any significant complement inhibitory activities. Preliminary immunohistochemical studies using the same antibody were carried out to determine the expression and distribution of KCP proteins in Kaposi's sarcoma.
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Cervantes, Daniela Viecceli. "Correlação entre a expressão celular de proteínas reguladoras do complemento e a resposta clínica de uma coorte de pacientes com artrite reumatoide tratada com rituximabe." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/87188.
Повний текст джерелаАнотація:
OBJETIVOS: Correlacionar o nível de expressão das proteínas reguladoras do complemento (Cregs) CD55, CD59, CD35 e CD46 nos linfócitos B em uma coorte de pacientes com artrite reumatoide (AR) iniciando terapia com rituximabe (RTX) com a depleção e tempo de repopulação destas células no sangue periférico, associando, ainda, o nível de expressão destas proteínas à resposta clínica conforme os critérios do Colégio Americano de Reumatologia (ACR). MÉTODOS: Dez pacientes com AR receberam duas infusões de RTX 1g separadas por intervalo de 14 dias. Análises imunofenotípicas para detecção de CD19, CD55, CD59, CD35 e CD46 foram realizadas pré-infusão e após 1, 2, 6, 12, 18 e 24 meses ou até recaída clínica. Depleção de linfócitos B no sangue periférico foi definida como valor de CD19 menor que 0,005x109/l no total de leucócitos. Resposta ACR20 em 6 meses foi considerada positiva e recaída clínica foi definida como perda dessa resposta. A não obtenção de ACR20 em 6 meses foi considerada falha de resposta ao tratamento. RESULTADOS: Dez mulheres com mediana de 49 anos e DAS28 basal de 5,6; nove delas soropositivas para fator reumatoide foram acompanhadas. Repopulação de linfócitos B ocorreu em 2 meses em cinco pacientes e em 6 meses nas demais. Houve correlação entre o nível de expressão basal de CD46 com o tempo de repopulação (coeficiente de correlação de -0,733, p=0,016). Tendência semelhante foi detectada com CD35, porém sem significância estatística (coeficiente de correlação de -0,522, p=0,12). Não houve associação entre resposta clínica e expressão das proteínas regulatórias do complemento. CONCLUSÕES: Expressão aumentada de CD46 foi preditora de repopulação mais precoce de linfócitos B em pacientes com AR tratados com RTX. Estudos com amostras maiores serão necessários para avaliar associação das demais Cregs.OBJECTIVES: To correlate the level of expression of the complement regulatory proteins (Cregs) CD55, CD59, CD35, and CD46 on B cells from a cohort of 10 patients with rheumatoid arthritis (RA) initiating treatment with rituximab (RTX) with the depletion and time of repopulation of these cells in peripheral blood, additionally correlating the level of expression of these proteins to clinical response according to the criteria of the American College of Rheumatology (ACR). METHODS: Ten patients with RA received two 1g RTX infusions within 14 day intervals. Immunophenotype analyses for CD19, CD55, CD59, CD35 and CD46 were performed before the infusion and at 1, 2, 6, 12, 18 and 24 months or until recurrence. Depletion of B cells on peripheral blood was defined as the CD19 count < 0.005x109/l. ACR20 at 6 months was considered a good clinical response and recurrence was defined as loss of this response. RESULTS: Ten women with median age of 49 years and basal DAS28 of 5.6 were monitored; 9 were seropositive for rheumatoid factor. Repopulation of B cells occurred within 2 months in 5 patients and within 6 months in the remaining women. There was correlation between the basal level of CD46 expression and the time to achieve repopulation (correlation coefficient -0.733, p=0.016). A similar trend was observed with the CD35, but without statistical significance (correlation coefficient - 0.522, p=012). There was no association between clinical response and the complement regulatory proteins. CONCLUSIONS: Increased CD46 expression predicted earlier repopulation of B cells in RA patients treated with RTX. Studies with larger samples are necessary to assess the association with the other Cregs.
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Carneiro, Alessandra Vasconcelos Araújo Rodrigues. "A criação de agência reguladora para o setor de seguros privados, resseguro, previdência complementar aberta e capitalização na percepção de executivos do setor." reponame:Repositório Institucional do FGV, 2016. http://hdl.handle.net/10438/17052.
Повний текст джерелаАнотація:
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O presente trabalho tem por objeto o estudo do modelo de governança da Superintendência de Seguros Privados – Susep, autarquia comum, confrontando-o com o modelo de autarquia especial, principalmente com o de agência reguladora, espécie daquele. O estudo teve origem em pesquisa exploratória, por meio da realização de entrevistas com executivos que atuam e possuem larga experiência no setor de seguros privados, resseguro, previdência complementar aberta e capitalização. Conforme as observações colhidas nas entrevistas, os principais problemas característicos do modelo de governança atual da Susep são ausência de independência orgânica e de autonomia financeira e orçamentária. O presente trabalho aprofundou na literatura nacional a compreensão dessas características no âmbito das agências reguladoras federais brasileiras, em contraste com as características atuais peculiares ao modelo de governança de autarquias comuns. O modelo das agências reguladoras foi escolhido pois a maioria dos próprios entrevistados manifestou entendimento no sentido de que o atual modelo de governança da Susep está ultrapassado e que a adoção do modelo de agência reguladora seria o mais adequado para o setor. Foram consultadas a legislação e doutrina especializada em agências reguladoras, Direito Tributário e Direito Econômico, bem como examinados acórdãos do Tribunal de Contas da União e pesquisas, relatórios e estudos nacionais já realizados nas searas da independência orgânica e da autonomia financeira e orçamentária das agências reguladoras federais brasileiras. Também foram analisados diversos projetos de lei em tramitação no Congresso Nacional, que propõem alterações na estrutura organizacional das agências reguladoras federais brasileiras e nas leis que tratam da gestão financeira e orçamentárias dessas agências. Por fim, concluiu-se que, embora a criação de uma agência reguladora para o setor de seguros privados, resseguro, previdência complementar aberta e capitalização possa contribuir para a superação de problemas associados ao modelo atual de governança da Susep, tal modelo não trará uma solução definitiva para os problemas atualmente existentes na Susep no que diz respeito à ausência de independência orgânica e de autonomia financeira e orçamentária do órgão. Além disso, embora o modelo de agência reguladora possa apresentar vantagens em relação ao modelo de autarquia comum, o modelo de governança das agências reguladoras federais brasileiras necessita ser aperfeiçoado para que se assegure maior independência e efetiva autonomia financeira e orçamentária.
This study's purpose is the study of the governance model of the Superintendency of Private Insurance - SUSEP, common autarchy, confronting it with the special autarchy, mainly with the regulatory agencies. The study originated in exploratory research through interviews with executives who work and have extensive experience in the private insurance industry, reinsurance, open private pension and capitalization. As the observations made in interviews, the main characteristic problems of the current governance model Susep are no organizational independence and financial and budgetary autonomy. This work has deepened in the national literature understanding these characteristics within the brazilian federal regulatory agencies, in contrast to the current peculiar characteristics of the governance model of common autarchy. The model of regulatory agencies was chosen because most of the interviewees expressed understanding in the sense that the current governance model of Susep is outdated and that the adoption of the regulatory agency model would be the most appropriate for the sector. Specialized law and doctrine regulatory agencies were consulted, so as Tax and Economic Laws. There were examinated judgments of the Court of Audit and researches, national reports and studies carried out in the fields of organic independence and financial autonomy and budget of brazilian federal regulatory agencies. There were also analyzed several bills pending in Congress that propose changes in the organizational structure of the brazilian federal regulatory agencies and laws dealing with financial management and budget of these agencies. Finally, it was concluded that although the creation of a regulatory agency for the private insurance industry, reinsurance, open private pension and capitalization can contribute to overcoming problems associated with the current model of governance of Susep, such a model will not bring a definitive solution to the current problems in the Susep regarding the lack of organizational independence and financial and budgetary autonomy of the organ. Furthermore, although the regulatory agency model may present advantages over common autarchy model, the governance model of the brazilian federal regulatory agencies needs to be improved to ensure greater independence and effective financial and budgetary autonomy.
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Pandya, Pankita Hemant. "HIF-1α regulates CD55 expression in airway epithelium". 2015. http://hdl.handle.net/1805/8002.
Повний текст джерелаАнотація:
Indiana University-Purdue University Indianapolis (IUPUI)Rationale: CD55 down-regulation on airway epithelium correlates with local complement activation observed in hypoxia-associated pulmonary diseases. Therefore, we hypothesized that induction of hypoxia inducible factor 1 alpha (HIF-1α) in hypoxic airway epithelium, mediates CD55 down-regulation. Methods: Chetomin and HIF-1α siRNA inhibited HIF-1α in hypoxic SAECs (1% O2), and mice lungs (10% O2). DMOG mediated HIF-1α stabilization in normoxic SAECs and mice lungs (21% O2). Transduction of SAECs with AdCA5 also stabilized HIF-1α. CD55 and CA9 transcripts were measured by RT-PCR. CD55 and HIF-1α protein expression was assessed by western blots. In vivo, immunohistochemistry (IHC) confirmed CD55 and HIF-1α expression. C3a and C5a levels in bronchoalveolar lavage fluid (BALF) were measured by ELISA. Results: HIF-1α was induced in 6 hour hypoxic SAECs (p<0.05), but CD55 transcripts were repressed (p<0.05). CD55 protein was down-regulated by 72 hours (p<0.05). CA9 transcripts were elevated by 48 -72 hours (p<0.05 and p<0.01, respectively). In vivo, CD55 transcripts and protein were down- regulated by 24 hours post-hypoxia (p<0.01) which corresponded to complement activation (p<0.05) in BALF. However, CA9 was increased (p<0.01). Chetomin (100nM) treatment in 6 hour hypoxic SAECs, recovered CD55 transcripts (p<0.01) and protein (p<0.05), but down-regulated CA9 (p<0.05). Similarly, in vivo chetomin (1mg/ml) treatment recovered CD55 protein (p<0.01) and down-regulated CA9 (p<0.01). Silencing HIF-1α (50nM) in hypoxic SAECs restored CD55 transcripts by 6 hours (p<0.05), and protein expression by 24 hours (p<0.05). However, CA9 was repressed (p<0.01). In vivo silencing of HIF-1α (50µg) restored CD55 protein expression (p<0.05) but down-regulated CA9 (p<0.05). Stabilizing HIF-1α in normoxic SAECs via DMOG (1µM), down-regulated CD55 transcripts and protein (p<0.01), but increased CA9 within 6-24 hours (p<0.05 and p<0.01, respectively). HIF-1α induction by DMOG (1mg/ml) in normoxic mice lungs down-regulated CD55 transcripts (p<0.01) and protein (p<0.01), but increased CA9 (p<0.05). Induction of HIF-1α in AdCA5 (50 PFUs/cell) transduced normoxic SAECs, resulted in CD55 protein down-regulation (p<0.05), but increased CA9 (p<0.001). Conclusions: HIF-1α down-regulates CD55 on airway epithelium. Targeting this mechanism may be a potential therapeutic intervention for attenuating complement activation in hypoxic pulmonary diseases.
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Vaz, Da Silva Zoé. "Influenza A virus infection modulates membrane regulations of complement activation." Doctoral thesis, 2018. http://hdl.handle.net/10362/98066.
Повний текст джерелаАнотація:
"The complement system is a key component of the
immune response as it bridges innate and adaptive immunity.
Moreover, it also plays a crucial role in modulating the intensity of
immunological and inflammatory processes by communicating
with immune cells. These interactions are beginning to be fully
appreciated, and their identification is crucial, as excess
complement activation is associated with severe outcomes in
many infections. In order to avoid immune-mediated damage to
the host, the complement cascade must be tightly regulated. The
self-targeting deleterious effects of complement are avoided via a
series of complement regulators (C-regs). Amongst the C-regs
complement decay-accelerating factor (DAF/CD55) and CD59
block the complement cascade at the central and terminal points,
respectively, and localise ubiquitously at the apical surface of
polarised cells. The lack of DAF and CD59 is associated with
over-stimulation of complement resulting in increased
inflammatory responses and worse outcome in several models of
infection and autoimmunity. In this work we have focused on the
role of DAF and CD59 in the context of IAV infection(...)"
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Shen, Ching-Fen, and 沈靜芬. "Binding of Human Complement Regulator C4b-binding Protein/Protein S Complex to Streptococcus pneumoniae in Immune Activation." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/12392792104141124231.
Повний текст джерелаАнотація:
碩士國立成功大學
臨床醫學研究所
96
Streptococcus pneumoniae is the most common etiological agent of pneumonia in children and is responsible for a broad spectrum of diseases, such as sinusitis, otitis media, meningitis, peritonitis, and bacteremia. Complement activation plays a pivotal role in immune defense. However, complement evasion has been used as a defense mechanism for S. pneumoniae to against innate immunity. Complement regulator C4b-binding protein (C4BP), a classical pathway complement inhibitor, is essential for regulating complement activation. Pathogens such as Streptococcus pyogenes could bind to C4BP and then cause interference on complement activation to escape from immune attack. In this study, we first demonstrated that serum proteins C4BP and protein S bound to S. pneumoniae using immunostaining followed by flow cytometry. Depleting protein S decreased the C4BP binding upon bacterial surface, indicating that C4BP and protein S bound to S. pneumoniae in a complex form. Notably, C4BP/protein S-binding S. pneumoniae showed a decrease in the activation of complement as demonstrated by the detection of C3 deposition. However, these bacteria were more susceptible to macrophage-mediated phagocytosis while depletion of protein S from serum decreased these effects. Studies further showed that clinical isolates obtained from the different infectious sites displayed variable binding affinity to C4BP, while none of colonization isolates bound to C4BP. Those clinical isolates, which have higher C4BP binding ability, were more easily engulfed by macrophages than those without C4BP binding. In summary, C4BP is involved in the innate immune activation of pneumococcal infection, especially the complement activation and phagocytosis.