Dissertations / Theses on the topic 'Bone morphogenetic proteins'
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Thomas, Nicole. "Bone morphogenetic proteins and hair and wool follicle morphogenesis." Title page, contents and abstract only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09pht4592.pdf.
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Bibliography: leaves 119-135. A thesis which describes a study to establish the relative roles that the bone morphogenetic proteins BMP-2 and BMP-4 play in initiating hair and derived wool follicles by first establishing their expression patterns by in situ hybridisation and then manipulating them in vitro.
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Christison, Joseph George. "The role of bone morphogenetic proteins in otic specification /." Connect to title online (ProQuest), 2008. http://proquest.umi.com/pqdweb?did=1616787971&sid=1&Fmt=2&clientId=11238&RQT=309&VName=PQD.
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Thesis (Ph. D.)--University of Oregon, 2008.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 43-47). Also available online in ProQuest, free to University of Oregon users.
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Yin, Huiran. "Expression, purification, and characterization of the extracellular domain of human BMPR-II in solution : a dissertation /." San Antonio : UTHSC, 2007. http://proquest.umi.com/pqdweb?did=1436373301&sid=1&Fmt=2&clientId=70986&RQT=309&VName=PQD.
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Qualtrough, John David. "Bone morphogenetic proteins in human embryonal carcinoma cells." Thesis, University of Sheffield, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311810.
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Mowbray, Catriona. "Bone morphogenetic proteins and zebrafish inner ear development." Thesis, University of Sheffield, 2002. http://etheses.whiterose.ac.uk/14716/.
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This thesis describes the mRNA expression patterns of the Bone Morphogenetic Proteins (BMPs), downstream members of the BMP signal pathway, BMP antagonists and candidate target genes in the developing inner ear of wild type zebrafish. The crista Bmp expression pattern is conserved between four vertebrate species. However, unlike in chick, mouse and Xenopus laevis none of the hmps examined are macula markers in zebrafish. This thesis identifies sources of Bmp signalling (the cristae, the endolymphatic duct (ED) and the semicircular canals (SCC)) and possible sites of Bmp action (the cristae, posterior macula, SCC and the mesenchyme around the ED). It also provides the first description of the early stages of ED development, a structure only recently described at later stages in the zebrafish (8dpf), and two mRNA markers of this structure (bmp4 and dachA). In analysis of zebrafish mutants with defective cristae, the presence of cristae correlated with the expression of the hmps and msxc, a putative Bmp target. This suggests the Bmps are required to form cristae and express msxc. Gain and loss of function studies have also supported a role for the Bmps in the development of the posterior macula and SCc. Ectopic hBMP4 protein was applied to the otic vesicle via protein-coated beads. This inhibited the development of the posterior macula and SCC. However, these hBMP4 beads were not sufficient to induce the expression of ectopic msxc, generate ectopic cristae or rescue crista development in mutants. Beads coated in a BMP antagonist did not affect the development of endogenous cristae or the expression of endogenous msxc. Rescued swirl (bmp2b) mutant adult zebrafish exhibit a balance defect. Early stages of inner ear development in rescued embryos were found to progress normally up until 7dpf. However, it is not clear when the rescuing mRNA or protein degrades, and work done by others in the lab has shown that Bmp2b is required at later stages to form adult SCc. The ectopic hBMP4 experiments suggest that moderating levels of Bmp signalling may be required for normal development of the SCC at early stages.
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Young, Julia, and n/a. "Bone morphogenetic proteins are involved in controlling mammalian fertility." University of Otago. Department of Biochemistry, 2008. http://adt.otago.ac.nz./public/adt-NZDU20090112.122706.
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Transforming growth factor beta (TGFβ) superfamily members are involved in controlling mammalian fertility. The largest subset of the TGFβ superfamily are the bone morphogenetic proteins (BMP). BMP ligands signal through the type I and II BMP receptors and utilise the Smads1/5/8 phosphorylation cascade to control gene expression in the cell nucleus. Although BMPs act through the same pathway, they have the ability to activate unique sets of genes dependant on the identity of the ligand. In this study, HEK293T cells were challenged with BMP ligands for four hours and gene expression profiles were compared using microarray technology. The genes upregulated in the presence of BMP2, BMP4, BMP6 and BMP7 play roles in cellular proliferation and differentiation. These functions are critical stages in the successful development of an ovarian follicle whilst undergoing folliculogenesis. All of the BMP ligands investigated in this study were also observed to upregulate the expression of a small group of common genes indicating that a shared regulatory pattern occurs within the BMP pathway. Of these genes, Smad6 and Smad7, inhibitor of DNA binding proteins 1-4 (ID 1-4), and msh homeobox homolog 2 (MSX2) were previously known BMP target genes. However, none of the remaining genes upregulated by all BMPs were previously shown to be BMP targets.
The results from the microarray experiment were used as founding data for the in silico mining of novel genes not present on the array that may be differentially expressed in response to these ligands. The expression levels of several of the novel genes identified by in silico mining were then measured in vitro, however the results showed no differential expression in the HEK293T cells.
To apply the knowledge of the microarray studies to the tissue of interest, eight genes were selected for assessment in ovine granulosa cells. Four of the genes upregulated in response to BMP6 in HEK293T cells were also differentially expressed in primary ovine granulosa cell cultures in response to BMP6 addition.
The identification of several sheep breeds with mutations in TGFβ superfamily members has enabled investigations into the roles that specific TGFβ components play in controlling fertility. The highly fertile Booroola sheep has a substitution mutation in the type IB BMP receptor that results in an additive effect on ovulation rate. The Booroola mutation causes precocious maturation of ovarian follicles with fewer granulosa cells surrounding an enlarged oocyte, and carriers of the mutation have higher levels of circulating follicle stimulating hormone (FSH). BMPs have previously been shown to influence the regulation of FSH synthesis and secretion in the pituitary gland. In this study, primary pituitary cells were harvested and cultured from homozygous Booroola ewes and from wildtype ewes to determine if the mutation caused alterations in FSH secretion in vitro. The cells were collected 24 h following induction of luteolysis and cultured for 72 h prior to being challenged for 24 h with bone morphogenetic proteins (BMP2, BMP4, BMP6), growth and differentiation factor-9 (GDF9), transforming growth factor β1 (TGFβ1), activin-A and gonadotropin releasing hormone (GnRH). The levels of FSH and luteinising hormone (LH) were measured by radioimmunoassay and compared to the untreated controls. Primary pituitary cell cultures from Booroola ewes secreted less FSH than wildtype cells in the presence of BMP2, BMP4 and BMP6. These BMPs did not affect the FSH stores within the cells, or the levels of LH released. GDF9 appeared to act in a BMP-like manner by suppressing FSH secretion. The BMPRIB receptor however, was not found to co-localise with gonadotroph cells in either Booroola or wildtype pituitary tissues. These findings imply that the increased sensitivity of Booroola cells to BMP2, BMP4, BMP6, and GDF9 cannot be due to the direct action of the BMPRIB mutant Booroola receptor in the cells that synthesize FSH. The alternative type I BMP receptor to BMPRIB that can act in BMP signal transduction is BMPRIA. This receptor was also not found in gonadotroph cells of wildtype orBooroola ewes This is in contrast to findings in other flocks which have been shown to express BMPRIA in gonadotroph cells.
This study has identified unique sets of differentially regulated genes in response to BMP-2, 4, 6, and 7 as well as TGFβ1 in a human HEK293T cell culture system. Among the differentially expressed genes, a common set of 12 genes were upregulated by all BMP ligands. None of these genes were present in the TGFβ1 set. Selected genes were validated in ovine primary granulosa cell cultures, showing that the human cell culture system functions similarly to cells of biologial relevance in fertility. Within the pituitary gland, BMPs are shown to influence FSH secretion. The presence of the Booroola mutation enhances the BMP effects on gonadotroph cells, however the lack of BMPRIB on gonadotroph cells indicates that the effects are indirect.
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Mace, Peter, and n/a. "Biochemistry of ovine bone and morphogenetic proteins and receptors." University of Otago. Department of Biochemistry, 2006. http://adt.otago.ac.nz./public/adt-NZDU20070508.133410.
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The transforming growth factor (TGF)-β superfamily mediates a wide range of differentiation and developmental processes across many genera. GDF9 and BMP15 are expressed exclusively in the mammalian ovary and are the only TGF-β ligands that lack the conserved cysteine residue used for dimerisation. As a platform for studying the interactions between GDF9 and BMP15 and their receptors, BMPRII and BMPRIb, a variety of strategies were attempted to produce soluble and active proteins from recombinant systems. Both ligands and receptors showed a tendency to form insoluble aggregates when expressed in prokaryotic systems; however after extensive screening, quantities of biologically active GDF9 were produced using in vitro refolding. When expressed alone, either containing a histidine tag or as an untagged protein, the BMPRII ectodomain was deposited as insoluble inclusion bodies. This protein, subjected to in vitro refolding procedures, exhibited multiple species following anion exchange chromatography and size exclusion chromatography, as visualised on native PAGE. Separation of these species could be achieved using a MonoP matrix. One of these separated fractions, representing about 5% of the starting material, was amenable to crystallisation, and furthermore exhibited activity in a rat granulosa cell thymidine incorporation assay. Two different crystals forms of the extracellular domain of BMPRII were grown from the same protein batch under similar crystallisation conditions. Notably, the tetragonal form that grew more slowly possessed several disordered finger regions, while electron density for the entire molecule was clear in the orthorhombic form. The hydrophobic core of the ligand binding surface of BMPRII , as seen in both structures, resembles that of ActRII bound to BMP2. The A-loop of BMPRII, which is involved in ligand binding, lies in two different conformations in the two structures of BMPRII, mediated by a rearrangement in disulfide Cys94-Cys117. It is proposed here that the tetragonal form represents the ligand-bound receptor structure. Although the majority of the hydrophobic binding surface is shared with ActRII(b), it is likely that His87 and Tyr40 are unique residues that confer specificity in BMPRII ligand binding.
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Wise, Sarah B. "Bone morphogenetic proteins in teleost tooth development and evolution." Connect to online resource, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3256386.
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Dootson, Gina Elizabeth. "Pro-osteogenic effects of follistatin on bone morphogenetic proteins." Thesis, University of York, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437559.
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Al-Hourani, Kinda. "Antiviral functions of bone morphogenetic proteins and the activins." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:579bda45-7f98-447d-b2d7-0565a00d8995.
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Previous work in the Drakesmith lab has revealed a novel anti-HCV function of bone morphogenetic protein 6 (BMP6), a TGFβ-superfamily cytokine unrelated to type I IFN. Recombinant BMP6 is antiviral against both replication-competent HCV and a full-length genomic replicon model. Data presented in this thesis demonstrate that an anti-HCV effect extends to multiple BMPs and segregates with ability to ligate the type I BMP receptor. Canonically, the type I BMP receptor signals intracellularly via phosphorylation of SMAD1/5/8 transcription factors. Prior work in the lab shows that BMP6 exerts both type I IFN-dependent and type I IFN-independent antiviral effects. In terms of delineating mechanistic basis for the latter, we have formulated a model whereby BMP6 induces cell cycle arrest in phases characterized by reduced cytosolic nucleotide availability, and which are therefore less permissive to viral replication. A recent report indicates that another TGFβ-type cytokine, activin B, is able to signal through a nonclassical type I BMP receptor dependent mechanism. Activin A and B have multiple established roles in innate immunity and inflammatory responses. However, no direct link between activin A and B and the early response to viral infection has been described. Given their "immune precedent" within the literature, and their high level of structural and phylogenetic homology to the BMPs, both activin A and B represented promising candidates to explore for an antiviral effect. Our data indicate that activin A mRNA, encoded by the INHBA gene, is induced upon activation of RIG-I, MDA5 and TLR7/8 viral nucleic acid sensors in vitro, across multiple cell lines and also in PBMCs. In vitro infection of A549 lung adenocarcinoma-derived cells and Huh7 hepatoma-derived cells with the murine paramyxovirus Sendai Virus also elicits robust INHBA induction. In vitro dengue virus infection also elicits INHBA upregulation by Huh7.5 hepatoma cells. In vivo, infection of mice with influenza A PR8 also elicits induction of activin A message within the lung. Treatment of Huh7 cells with activin A increases transcription of multiple type I IFN transduction elements; moreover, co-incubation of Huh7 cells with IFNa and either activin A or B augments transcriptional induction of key anti-HCV enzymes. This boosting of type I IFN extends to a functional enhancement: activin A elicits a synergistic, dose-dependent enhancement of both type I and type III IFN's antiviral effect against a full-length HCV genomic replicon. In a full-length genomic replicon model of HCV, both activin A and B alone exert a potent, dose-dependent antiviral effect that is contingent upon signalling via type I BMP receptor. A component of the activins' antiviral effect does not require intact type I IFN signalling. A small-molecule inhibitor of signalling downstream of type I IFN receptor blocks the anti-HCV effect of IFNa but does not impair the antiviral effects of activin A. Both BMP6 and activin A exert dose-dependent antiviral effects against Hepatitis B Virus infection in vitro. Of note, SMAD1/5/8-binding sites have been identified in the promoter sequences of multiple antiviral Interferon Stimulated Genes (ISG), providing a possible route for the enhancement of ISG induction by the SMAD1/5/8 axis. Furthermore, strong topological homology exists between of the transactivation domains of the SMADs and Interferon Response Factors (IRF), which postulated to have diverged from a common ancestor in early metazoans. Preliminary bioinformatic analyses reveal striking parallels between the genome-wide binding profiles of activated SMAD1 and IRF1, including proximal to genes encoding antiviral effectors. The observations presented in this study may represent the first characterization of a non-IFN intracellular antiviral response in human cells, with implications for the development of targeted therapies against diverse viral diseases. Moreover, these data reveal a novel facet of activin biology, in addition to in part elucidating the nature of the genomic interactions between BMP-SMAD and IFNIRF signalling.
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Ahmed, Takiya Janice. "The role of bone morphogenetic proteins in otic specification /." Connect to title online (Scholars' Bank) Connect to title online (ProQuest), 2008. http://hdl.handle.net/1794/8447.
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Thesis (Ph. D.)--University of Oregon, 2008.Typescript. Includes vita and abstract. Includes bibliographical references (leaves 195-204). Also available online in ProQuest, free to University of Oregon users.
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Liu, Jin. "Increased CKIP-1 suppresses Smad-dependent BMP signaling to inhibit bone formation during aging." HKBU Institutional Repository, 2016. https://repository.hkbu.edu.hk/etd_oa/327.
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Emerging evidence indicates that the dysregulation of protein ubiquitination plays a crucial role in aging-associated diseases. Smad-dependent canonical BMP signaling pathway is indispensable for osteoblastic bone formation, which could be disrupted by the ubiquitination and subsequent proteasomal degradation of Smad1/5, the key molecules for BMP signaling transduction. However, whether the dysregulation of Smad1/5 ubiquitination and disrupted BMP signaling pathway are responsible for the age-related bone formation reduction is still underexplored. Casein kinase-2 interacting protein-1 (CKIP-1), also known as Pleckstrin homology domain-containing family O member 1 (PLEKHO1), is a previously identified ubiquitination-related molecule that could specifically target the linker region between the WW domains of Smurf1 to promote the ubiquitination of Smad1/5. Here, we found an age-related increase in the expression of CKIP-1 in bone specimens from either fractured patients or aging rodents, which was associated with the age-related reduction in Smad-dependent BMP signaling and bone formation. By genetic approach, we demonstrated that loss of Ckip-1 in osteoblasts could promote the Smad-dependent BMP signaling and alleviated the age-related bone formation reduction. In addition, osteoblast-specific Smad1 overexpression had beneficial effect on bone formation during aging, which could be counteracted after overexpressing Ckip-1 within osteoblasts. By pharmacological approach, we showed that osteoblast-targeted CKIP-1 siRNA treatment could enhance Smad-dependent BMP signaling and promote bone formation in aging rodents. Taken together, it suggests that the increased CKIP-1 could suppress Smad-dependent BMP signaling to inhibit bone formation during aging, indicating the translational potential of targeting CKIP-1 in osteoblast as a novel bone anabolic strategy for reversing established osteoporosis during aging.
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Weber, Markus. "Bone Morphogenetic Proteins (BMP) in der Embryonalentwicklung von Tribolium castaneum." Diss., [S.l.] : [s.n.], 2006. http://edoc.ub.uni-muenchen.de/archive/00006560.
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Din, Sarah. "The Protective Role of Bone Morphogenetic Proteins in Pulmonary Artery." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486283.
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Familial primary pulmonary arterial hypertension (FPAH) is associated with mutations in bone morphogenetic protein receptor II (BMPRII). The role of this mutation in vascular tone and structural remodelling in PAH is unknown. The aim of this thesis was.to determine the ability of BMPRII ligands to modulate the ET-1 system, which has been implicated in the p'athogenesis of FPAH. BMP2, BMP4 and BMP? were examined for their effects on ET-1 release by cultured pulmonary artery smooth muscle cells (PASMC). BMP? (100ng/ml) significantly reduced cytokine-induced ET-1 release. BMP2 and BMP4 had no effect on ET-1 release from these cells. The influence of BMPRII ligands on vascular tone in normal PA has not been investigated. Ring segments of PA setup in organ baths, were assessed for their response to ET-1 in the presence and absence of 1, 10 or 100nglml of BMP2, BMP4 and BMP? BMP? significantly inhibited contraction in response to ET-1 in a concentration-dependent manner. This effect was not seen with BMP2 and BMP4. It has been suggested that mature vascular. endothelium can give rise to SMCs . via a process called endothelial to mesenchymal transformation (EMT). l(llmunocytochemistry and western blotting showed that TGF-J3 induced EMT in PA endothelial cells (PAEC) was associated with decreased VE-cadherin and zonula occludens expression and a loss of EC morphology. BMP? was able to restore the expression of these proteins as well as the EC phenotype. In addition, this study also demonstrates BMPRII ligands are able to produce these effects via Smad protein signalling in PASMC and PAECs. These results suggest that BMP? may have a'role in regulating ET-1 release and ET-1 induced contraction in the normal pulmonary circulation. BMP? also maintains the morphology of PAECs. Genetic mutations in BMPRII may lead to a loss of these regulatory mechanisms and contribute to the pathogenesis and vascular remodelling associated with FPAH.
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Al-Samerria, Sarmed. "The role of bone morphogenetic proteins (BMPs) in ovarian function." Thesis, Curtin University, 2016. http://hdl.handle.net/20.500.11937/1567.
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Bone morphogenetic proteins (BMPs) have been reported to involve in the ovarian folliculogenesis through interacting with gonadotropin hormones. However, the mechanism of interaction is not clearly understood. The aim of the current study was to demonstrate the mechanism of interaction between BMPs and gonadotropins using different technical approaches. The outcomes of the current study demonstrate that BMPs involves directly and indirectly in regulating follicle development which opens an interesting opportunity to improve fertility and enhance reproductive life.
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Ramage, Samuel Cowan. "The role of secreted phosphoprotein-24 in osteoblast differentiation and matrix mineralization /." Available online after August 19, 2013, 2007. http://hdl.handle.net/10156/2291.
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Yong, Tseh-Hwan. "Apatite-polymer composites for the controlled delivery of bone morphogenetic proteins." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/33405.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2005."June 2005."
Includes bibliographical references.
Current treatment of bone defects due to trauma, cancer, or degenerative spine diseases involves the implantation of a bone graft. Autografts, which are harvested from the patient's own body, are associated with problems of limited availability and surgical morbidity. The use of allografts obtained from donors is also not desirable due to the risks of disease transmission and the costs of maintaining bone banks. The ideal solution would be to regenerate native bone to fill the defects. A group of potent growth factors known as bone morphogenetic proteins (BMPs) have been hailed as alternatives to bone grafts due to their ability to elicit new bone formation. Clinical use of BMPs involves loading the protein solution onto collagen sponges and subsequent implantation. However, these conventional collagen carriers show rapid clearance of BMPs within [approx.] 2 weeks, whereas bone healing is a longer process, especially in higher mammals. The poor BMP retention in collagen sponges may explain the greater response variability in higher mammals, ranging from full bone bridging within weeks to no bone union. These sponges are also not capable of tunable or multifactor release that could benefit healing in certain anatomic sites, e.g. avascular sites and prolonged non-unions. Hence, the motivation of this thesis is to develop new carriers that allow more efficacious and flexible delivery of BMPs to achieve bone healing.
(cont.) The carrier should ideally exhibit (i) sustained release to maintain the response and activity of bone-forming cells, (ii) low initial burst to avoid adverse effects of a bolus administration and to conserve the expensive growth factor, and (iii) tunable release to meter out BMPs at the desired rate. In particular, tunable release and low burst release have long been challenges in controlled delivery systems. A carrier that can offer such temporal control will be highly valuable to the delivery of other therapeutic proteins, drugs and genes as well. To this end, we have devised a novel composite of two biomaterials with proven track records: poly(lactic-acid-co-glycolic acid) (PLGA) and apatite. The controlled release strategy was based on the use of a biodegradable polymer with acidic degradation products to manipulate the dissolution of the basic apatitic component. Proteins were pre-adsorbed onto the apatitic component such that as the apatite dissolved, proteins were released. Apatite-PLGA composites were formed into microparticles by a solid-in-oil-in-water emulsion process. In contrast to polymeric microparticles prepared by the conventional water-in-oil-in-water emulsion process, these composite microparticles exhibited zero-order, low burst release.
(cont.) Low burst release was attributed to the affinity of the apatite for the protein; until the apatite was dissolved, the protein was sequestered and prevented from premature release. Accordingly, the use of apatite singly as a carrier would have led to extremely slow release. A model protein, bovine serum albumin (BSA), and a therapeutic protein, recombinant human BMP-2 (rhBMP-2), were encapsulated in these apatite-PLGA composite particles. The release profile was modified systematically by changing variables that affected polymer degradation and apatite dissolution, such as polymer molecular weight, polymer hydrophobicity, apatite loading, and apatite particle size. An increase in polymer molecular weight, apatite loading or apatite particle size reduced the release rate of both BSA and rhBMP-2. Interestingly, increasing polymer hydrophobicity diminished the release of BSA, but enhanced the release of rhBMP-2. Slower polymer degradation associated with greater polymer hydrophobicity might have decreased the total amount of protein released, but preserved a larger bioactive fraction due to milder pH conditions within the particles. A suitable particle formulation for sustained rhBMP-2 delivery was identified as protein-sCAP-59 kD PLGA.
(cont.) When rhBMP-2 was encapsulated in these composite microparticles, it was released in a sustained fashion over 100 days. More importantly, the bioactivity of the protein was retained, as evaluated by its ability to induce the differentiation of mesenchymal stem cells toward the osteoblast lineage. Specifically, the levels of osteoblastic phenotype markers such as alkaline phosphatase (ALP) and osteocalcin were found to be significantly elevated compared to the controls. In contrast, rhBMP-2 released from conventional collagen sponges after 2 weeks did not increase the ALP expression over the controls. Protein-loaded composite microparticles were dispersed in secondary matrices, either gelatin or collagen sponges, for bone tissue engineering. Multifactor release from these scaffolds was possible through the incorporation of different sets of composite microparticles containing different proteins and exhibiting distinct release profiles. Collagen sponges injected with rhBMP-2-loaded composite microparticles were implanted in subcutaneous sites in rats. These composite collagen sponges stimulated a much higher degree of cellularity and vascularity than the controls without BMPs. The increased vascularity might be evidence of the angiogenic activity of rhBMP-2 at low concentrations in vivo.
by Tseh-Hwang Yong.
Ph.D.
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Ye, Lin. "Bone morphogenetic proteins and their receptors in the development of bone metastasis in prostate cancer." Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/55718/.
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Bone morphogenetic proteins (BMPs) are key factors in bone formation. Selective BMPs have been implicated in the progression and in particular the bone metastasis of prostate cancer. However, the exact role of the BMPs and the signaling pathways initiated by BMP in cancer including prostate cancer are poorly understood. This study aims to investigate the role of a panel of newly discovered BMPs in prostate cancer and the possible signal transduction pathways in prostate cancer. In the current study, we examined the expression of certain BMPs, the BMP receptors and putative intracellular signaling molecules in prostate cell lines using RT-PCR, which allowed us to design the strategy of in vitro experiments. Reduced/loss of expression of both BMP-9 and BMP-10 was seen in high grade foci in prostate cancer specimens using immunohistochemical staining. Aberration of BMP receptors and certain antagonists were also seen. This suggests that these BMPs and the receptors may play profound roles in the development and progression of prostate cancer. A panel of prostate cancer cell lines were subsequently established, with which either a specific BMP or BMP receptor were genetically manipulated. Firstly, knock-down of BMP receptor-IB (BMPR-IB) and BMP receptor-II (BMPR-II) using ribozyme transgenes, resulted in an increase of cellular proliferation, which suggested that both receptors are responsible in mediating the inhibitory effects of BMPs on cell growth in prostate cancer cells. Secondly, the reduction of endogenous BMP-7 using a hammerhead ribozyme transgene led to stimulation of cellular motility and adhesion of prostate cancer cells. This was found to be the result of a feedback down-regulation of both Noggin and Follistatin, antagonists of BMPs, after loss of BMP-7. Thus, a novel mechanism underlying the action of BMP-7 was established: the endogenous antagonist dependent action of BMP-7. The study went on to demonstrate that BMP-9 and BMP-10 can inhibit cellular growth, invasion and migration using in vitro function assays. Recombinant human BMP-9 and BMP-10 were also generated using affinity chromatography and will be utilised in the future investigation. In conclusion, endogenous BMP antagonist is an important mechanism in the action of BMPs in cancer cells. Furthermore, BMP-9 and BMP-10 function as potential tumour suppressors in prostate cancer. BMPs and BMP receptors signaling play profound roles in prostate cancer. These molecules and their antagonist may have important therapeutic implications in disease specific bone metastasis.
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Song, Hannah. "Endothelial bone morphogenic protein 4 and bone morphogenic protein receptor II expression in inflammation and atherosclerosis." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/28258.
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Thesis (M. S.)--Biomedical Engineering, Georgia Institute of Technology, 2008.Committee Chair: Hanjoong Jo; Committee Member: Ajit P. Yoganathan; Committee Member: Andrew P. Kowalczyk; Committee Member: David G. Harrison; Committee Member: Kathy K. Griendling
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Chan, Wai-long, and 陳慧朗. "The protective role of bone morphogenetic protein-7 against mesangial cell injury in IgA nephropathy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41290872.
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Brown, Elaine Hilary. "Chemical modification of 5-aminolevulinic acid for improved photodynamic therapy." Thesis, University of St Andrews, 1999. http://hdl.handle.net/10023/14513.
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5-Aminolevulinic acid (ALA), one of the body's naturally occurring molecules in the biosynthetic pathway to haem, is being used in Photodynamic Therapy (PDT), a new approach to the treatment of cancer. It is a highly reactive molecule, which, upon standing in solution, dimerises to give 2,5-di-(beta-carboxyethyl) pyrazine. This reaction, and other similar ones, have been studied in some detail as it remains a major problem in the clinic, lowering the dose of active drug being administered and forming a molecule of which the toxicology is not known. The initial product of dimerisation is a dihydropyrazine, which is immediately oxidised in air to give a pyrazine. The chemistry of dihydropyrazines has also been investigated. The chemical synthesis of ALA itself has been optimised and derivatives of the molecule have been prepared to try to prevent this dimerisation from occurring and, potentially, increase the tissue selectivity of the drug. Twelve derivatives of ALA have been prepared and biologically tested for their activity in PDT.
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Chan, Wai-long. "The protective role of bone morphogenetic protein-7 against mesangial cell injury in IgA nephropathy." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41290872.
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Bokobza, Sivan. "The role of bone morphogenetic proteins and their signalling in human cancers." Thesis, Cardiff University, 2010. http://orca.cf.ac.uk/55464/.
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Both endogenous and exogenous GDF-9 led to a promotion in prostate cancer cell adhesion, invasion, motility, and growth. GDF-9 mediated growth promotion was shown to correlate with an increase in cell cycle progression via up-regulation of Cyclin D1, and protection from apoptosis in a Smad-independent manner. Furthermore, GDF-9 associated cell adhesion, motility, and invasion was shown to involve FAK, paxillin, and Rho-ROCK signalling, as well as EMT and its associated inducers. These effects promote the aggressiveness of PC-3 cells, aiding in their progression and possibly metastasis. These results suggest that GDF-9 is involved in prostate cancer progression by activation of a complex network of signalling pathways and molecules. This provides further proof of the importance of BMP signalling, and suggests that perhaps novel treatments for prostate cancer based on BMPs should be investigated. In addition, it sheds some light on the use of BMPs as prognostic indicators of disease, aiding in diagnosis, and perhaps future forms of treatment.
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Hornstein, Alexandra Marielisa [Verfasser]. "Einfluss bestimmter bone morphogenetic proteins auf die endotheliale Permeabilität / Alexandra Marielisa Hornstein." Berlin : Freie Universität Berlin, 2016. http://d-nb.info/1090877927/34.
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Cannon, John Edward. "The role of bone morphogenetic protein signalling in zebrafish vascular development." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609960.
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Peirce, Vivian Julia. "Regulation of adipose tissue function by bone morphogenic protein 8b." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709428.
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Phan, Tuan (Tony). "Functional characterisation of an osteoclast-derived osteoblastic factor (ODOF)." University of Western Australia. School of Surgery and Pathology, 2004. http://theses.library.uwa.edu.au/adt-WU2005.0028.
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[Truncated abstract] Bone is a living tissue and is maintained by the coordinate action of osteoblasts and osteoclasts. The intercellular communication between these two cells is the quintessential mechanism in bone remodelling. Unfortunately, the importance of this interaction is often neglected and its significance is only realised when disruption of this “cross-talk” results in debilitating bone diseases. Additionally, the number of known proteins that are involved in this “cross-talk”, especially those that are osteoclast-derived, and act specifically on osteoblasts, is limited. This discrepancy leads to the question: Can osteoclasts directly control the growth and function of osteoblastic cells by expressing specific proteins that bind directly to osteoblasts? If so, is it possible to use these proteins to control and, possibly, treat bone disease? The objective of this thesis is to identify and characterise osteoclast-derived factors that can modulate bone homeostasis, as well as contribute to the intercellular communication between osteoblasts and osteoclasts ... Collectively, the data in this thesis culminates in one important conclusion: the identification of a novel paracrine secretory factor that has the potential to directly induce the formation of bone. These findings represent the first ever characterisation of a protein that allows the osteoclasts to directly control the growth and function of osteoblasts. Due to the potential function of ODOF to induce bone formation, this protein may be used therapeutically to treat bone disease.
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Li, Ruixi, and 李瑞曦. "Anti-inflammatory role of bone morphogenetic protein 7 in the diabetic kidney." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2015. http://hdl.handle.net/10722/211143.
Full textAbstract:
Diabetic nephropathy (DN) has become the leading cause of end stage renal disease (ESRD) in developed countries, in which over 90% of the diabetes burden is type 2 in origin. Despite the ever advancing knowledge in the pathogenetic mechanisms of DN, a specific treatment is still lacking and management using contemporary approaches or exploiting newly described therapeutic targets are largely unrewarding. BMP-7 has been reported to confer renal protective effects in acute and chronic kidney disease models, but its potential utility in type 2 diabetic nephropathy remains unknown. In this work, therefore, I hypothesized that BMP-7 confers renal protection that will be explore in vitro in AGE-induced tubular epithelial cells, and in vivo in a murine type 2 DN model. Primary human proximal tubular epithelial cells (PTECs) were growth-arrested and exposed to glycated human serum albumin (AGEs) with or without BMP-7. Inhibitors of different signaling pathways were used to dissect the involvement of each pathway. Nine-week-old db/db mice and their db/m littermates underwent uninephrectomy (Unx) or sham operation, and received BMP-7 (300 μg/kg body weight) or vehicle treatment intraperitoneally every other day for 8 weeks before sacrifice. In cultured human PTECs, exposure to AGEs induced overexpression of ICMA-1, MCP-1, IL-8 and IL-6, involving activation of at least p44/42 and p38 MAPK signaling. BMP-7 dose-dependently attenuated AGE-induced up-regulation of ICMA-1, MCP-1, IL-8 and IL-6 at both mRNA and protein levels. Moreover, BMP-7 suppressed AGE-induced p38 and p44/42 MAPK phosphorylation and reactive oxygen species production in PTECs. Compared with vehicle control, Unx db/db mice treated with BMP-7 for 8 weeks had significantly lower urinary albumin-to-creatinine ratio (3549±816.2 μg/mg vs. 8612±2037 μg/mg, p=0.036), serum BUN (33.26±1.09 mg/dL vs. 37.49±0.89 mg/dL, p=0.006), and renal cortical expression of ICMA-1 and MCP-1 at both gene and protein levels. PAS staining of kidney tissue showed less severe tubular damage and interstitial inflammatory cell infiltration in the BMP-7-treated group. In conclusion, this series of experiments demonstrated that BMP-7 attenuates tubular pro-inflammatory responses in diabetic kidney disease by suppressing oxidative stress and multiple signaling pro-inflammatory pathways including p38 and p44/42 MAPK. These observations are largely translated in animals with diabetic kidney inflammation. The potential application of BMP-7 as a therapeutic molecule in diabetic nephropathy warrants further investigation and development.published_or_final_version
Medicine
Doctoral
Doctor of Philosophy
29
Böhler, Nina. "Auswirkungen von Gewichtsreduktion und einem kontrollierten Trainingsprogramm auf die Serumkonzentration der Bone morphogenetic proteins (BMPs) -2 und -4 bei Patienten mit Typ 2 Diabetes." Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-149795.
Full textAbstract:
Adipositas und Typ-2-Diabetes sind häufige Erkrankungen des Stoffwechsels. Zur Basistherapie der Adipositas und des Typ-2-Diabetes gehören eine gesunde Ernährungs- weise und die Erhöhung der körperlichen Aktivität unter anderem mit dem Ziel der Gewichtsreduktion. Vermehrte Bewegung führt neben der Verbesserung der körperlichen Leistungsfähigkeit zur Fettmassenreduktion, Verbesserungen der Hyperglykämie, Lipo- proteinstoffwechsels und des Adipokinprofils.
Bone morphogenetic proteins (BMPs) werden im Fettgewebe produziert und spielen eine wichtige Rolle in der Adipogenese und Transdifferenzierung von Adipozyten. Während ein Zusammenhang zwischen der BMP-7-Serumkonzentration und Adipositas vor kurzem belegt wurde, ist bisher nicht bekannt, ob weitere BMPs wie BMP-2 und -4 mit Adipositas und Typ-2-Diabetes assoziiert sind. Ziel dieser Arbeit war es deshalb zu untersuchen, ob die BMP-2 und -4 Serumkonzentrationen im Zusammenhang mit Körpergewicht, Fett- verteilung und Parametern des Glukosestoffwechsels bei Patienten mit Adipositas und Typ-2-Diabetes (n=213) stehen. Im Rahmen von drei Interventionsstudien wurde der Einfluss einer hypokalorischen Ernährungsweise über sechs Monate (n=19), eines 45,3 ± 7,4 kg Gewichtsverlustes ein Jahr nach bariatrischer Chirurgie (n=32) sowie eines zwölf- wöchigen Trainingsprogramms (n=60) auf die BMP-2- und -4-Serumkonzentrationen untersucht. Zusätzlich wurde die BMP-2-und -4-mRNA-Expression in humanen omentalen und subkutanen Fettgewebsproben von 161 Patienten charakterisiert.
Die BMP-2- und -4-Serumkonzentrationen und die BMP-2- und -4-mRNA-Expression im viszeralen Fettgewebe korrelieren signifikant mit dem BMI und dem Körperfettgehalt.
Zirkulierende BMP-4-Spiegel sind geschlechtsabhängig und bei Patienten mit T2D signifikant niedriger als bei gesunden Kontrollpatienten. Sowohl eine moderate Gewichts- reduktion durch kalorienreduzierte Ernährung als auch ein Gewichtsverlust von 45,3 ± 7,4 kg nach bariatrischer Chirurgie führen zu einer signifikanten Reduktion der zirkulierenden BMP-2- und -4-Spiegel. Das zwölfwöchige Trainingsprogramm führte lediglich zu einer signifikanten Reduktion der BMP-2-Serumkonzentration und zu signifikanten Ver- besserung der Leistungsfähigkeit, von Parametern des Glukosestoffwechsels und der Serumkonzentrationen von Adiponektin und Interleukin-6.
Zusammengefasst zeigen die Daten, dass erhöhte Serumkonzentrationen von BMP-2 und 4 mit Adipositas assoziiert sind und durch Gewichtsreduktion und Erhöhung der körperlichen Aktivität verringert werden können. Die BMP-2- und -4-mRNA-Expression im viszeralen Fettgewebe kann zu erhöhten Serumkonzentrationen dieser Adipokine bei viszeraler Fettverteilung beitragen.
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Hoang, Quyen Quoc Yang Daniel. "Crystal structure and hydroxyapatite binding of porcine osteocalcin /." *McMaster only, 2003.
Find full text
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Brown, Monica Anne. "Structural and functional analysis of bone morphogenetic proteins crystal structure of bone morphogenetic protein-9, binding studies with pro-domain and receptors, and mutational studies in Drosophila decapentaplegic /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p3304428.
Full textAbstract:
Thesis (Ph. D.)--University of California, San Diego, 2008.Title from first page of PDF file (viewed June 18, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 62-72).
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Zhou, Lixiong, and 周立雄. "Differential action of bone morphogenetic protein BMP-2 and BMP-7 on nucleus pulposus cells of intervertebral disc." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/209509.
Full textAbstract:
Low back pain (LBP) is associated with intervertebral disc (IVD) degeneration and exerts enormous socioeconomic burdens on the society. The nucleus pulposus (NP) is the structural and functional core of the IVD, and plays vital roles in its homeostasis. Although the etiology of IVD degeneration is not fully understood, the cellular changes of the NP have been proposed to be associated with degeneration. Conventional management for IVD degeneration primarily targets to relieve LBP and other symptoms without restoring or preserving disc function. Novel therapeutic strategies have emerged with an aim to retard or even reverse disc degeneration. In particular, the use of growth factors, such as the bone morphogenetic proteins (BMP), has received considerable attention due to their anabolic effects on extracellular matrix (ECM) synthesis by NP cells.
BMP-2 and BMP-7 are of great interest for their involvement in osteogenesis, chondrogenesis, and development and maintenance of the IVD. To date, the benefits of BMP-2 on disc degeneration are controversial, given the inconsistent findings from animal model studies. The effectiveness of BMP-7 in disc repair, however, has been well demonstrated both in vitro and in vivo. A better understanding of the differences between BMP-2 and BMP-7 regulatory action on NP cells may facilitate future applications of BMP in disc repair/regeneration.
This study hypothesized that BMP-2 and BMP-7 act differentially on human NP cells via different signal transduction processes. The differential effect of BMP-2 and BMP-7 was first tested in bovine NP cells using a three-dimensional culture system (alginate beads). Both BMP-2 and BMP-7 enhanced ECM production and phenotypic characteristics of bovine NP cells. Notably, BMP-7 was significantly more potent than BMP-2 in this regard. The effects of BMPs were further tested on non-degenerated (ND-NP) and degenerated (D-NP) human NP cells. The DMMB assay revealed that BMP-7 exerted a superior up-regulatory action on GAG production of D-NP cells compared to BMP-2. Furthermore, the overall response of D-NP cells to BMP-2 and BMP-7 was significantly lower than ND-NP cells.
Immunohistochemical staining and quantitative RT-PCR assays demonstrated that D-NP cells possess a more fibroblastic and less chondrocyte-like phenotype than ND-NP cells. At the mRNA level, the BMP receptor BMPR1A was not expressed in D-NP cells. BMP-7, but not BMP-2, induced expression of BMPR1A in D-NP cells. On the other hand, gene expression of selected TGF-β pathway components and hypoxia pathway components were significantly up-regulated by BMP-2 but down-regulated by BMP-7. These findings suggest that D-NP cells can activate differential molecular cascades in response to BMP-2 and BMP-7.
In conclusion, this study showed a superior effect of BMP7 in up-regulation of classical BMP signaling components including BMP receptor BMPR1A. The reduced responsiveness of D-NP cells to BMP-2 and BMP-7 stimulation may be related to a different expression pattern of BMP receptors. This study provides insights into the differential regulatory actions of BMP-2 and BMP-7 on human NP cells and facilitates the future application of BMPs in managing disc degeneration.published_or_final_version
Orthopaedics and Traumatology
Doctoral
Doctor of Philosophy
33
Wardle, Fiona Claire. "Regulation of the BMP signalling pathway by BMP-1 related metalloproteases." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287477.
Full text
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Anantharam, Andrea Brenner. "The role of BMP signaling in the segmentation of the urinary tract /." Access full-text from WCMC, 2007. http://proquest.umi.com/pqdweb?did=1490074011&sid=13&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Campisi, Paolo. "Characterization of the expression of bone morphogenetic proteins during distraction osteogenesis of the mandible." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=32980.
Full textAbstract:
Distraction osteogenesis is a form of in vivo tissue engineering used to lengthen bone. Bone morphogenetic proteins (BMPs) are known mediators of bone formation during the distraction of enchondral bones. Their role in the distraction of membranous bones remains unknown. A rabbit model was used to characterize the expression of BMP-2, 4 and 7 during mandibular distraction osteogenesis. Fourteen animals were subjected to a defined distraction protocol. At weekly intervals, two rabbits were sacrificed and the generate bone harvested for radiographic, bone densitometric, histologic and immunohistochemical analyses. The results demonstrate that during distraction, bane forms primarily by intramembranous ossification. BMP-2 and 4 were maximally expressed in osteoblastic cells during the distraction period and in chondrocytes during the consolidation period. The pattern of mandibular BMP expression was different than previously described for long bones. Understanding the pattern of BMP expression may guide the strategic administration of recombinant BMPs to enhance the rate and quality of bone formation during distraction osteogenesis thereby shortening the time required for consolidation of the generate bone.
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Fuller, Molly Lynn. "The Role of Bone Morphogenetic Proteins in Reactive Gliosis after Demyelinating Spinal Cord Lesions." Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1183990990.
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Kapanen, A. (Anita). "Biocompatibility of orthopaedic implants on bone forming cells." Doctoral thesis, University of Oulu, 2002. http://urn.fi/urn:isbn:9514266064.
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Abstract
Reindeer antler was studied for its possible use as a bone implant material. A
molecular biological study showed that antler contains a growth factor promoting
bone formation. Ectopic bone formation assay showed that antler is not an equally
effective inducer as allogenic material.
Ectopic bone formation assay was optimised for biocompatibility studies of
orthopaedic NiTi implants. Ti-6Al-4V and stainless steel were used as reference
materials. The assay showed differences in bone mineral densities, with superior
qualities in NiTi. The rate of endochondral ossification varied between the
implants, NiTi ossicles had larger cartilage and bone areas than ossicles of the
two other materials.
The cytocompatibility of NiTi was studied with three different methods. Cell
viability, cell adhesion and TGF-β1 concentration were assessed in
ROS-17/2.8 cell cultures. Cells grown on NiTi had better viability than cells
grown on pure nickel or stainless steel. Cell attachment on the materials was
studied with paxillin staining of focal contacts. The number of focal contacts
was clearly higher in cells grown on NiTi than in cells grown on pure titanium,
pure nickel or stainless steel. TGF-β1 concentration was measured with
ELISA. The results showed that there was only some minor variation between NiTi,
pure titanium and stainless steel. Nickel showed a lower TGF-β1
concentration. Taken together, these results suggest that NiTi is well tolerated
by ROS-17/2.8 cells. The cytocompatibility of stainless steel is not so good as
that of NiTi.
The same tests were used to study the effects of the surface roughness of the
implant on cytocompatibility. Three different surface roughness grades were
compared in cell cultures on NiTi and titanium alloy discs. Titanium alloy was
subjected to two different heat treatments, to compare the effects of the
treatments on cytocompatibility. The studies showed that NiTi had a lesser impact
on cell viability and attachment than titanium alloy. Further, rough NiTi was
found to be a better tolerated surface than the others. In this study, heat
treatment of titanium alloy at +850° C did not interfere with cell viability
or attachment, as did the +1050° C treatment of the alloy. On the contrary,
TGF-β1 concentrations decreased on the +850° C treated alloy and were
approximately same on the +1050° C treated alloy and on NiTi.
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Zhao, Xiaoli, and 赵晓丽. "BMP2 gene delivery mediated by chitosan-ss-PEI non-viral vector and investigation of BMP2 signaling regulation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47246078.
Full textAbstract:
Osteoporotic fractures are still the major health concerns in many developed
societies especially when the incidence of that tremendously increased with the aging
population. However, the outcomes of osteoporotic fracture treatment have not been
entirely satisfactory due to the poor quality of bone substance. Inspiringly, bone
morphogenetic protein 2 (BMP2) with the ability to accelerate bone formation
showed advantages over the conventional treatment. The only problem needed to
overcome is its short half-life which resulted in the requirement of readministration
and extremely high cost. As a solution to that, gene therapy provides a promising way
to sustainably release this protein at the regeneration site. Since viral vectors have
been hampered by genetic toxicity and immunogenicity, nanoscaled non-viral vectors
offer an attractive means for gene delivery.
Chitosan as non-viral vector has been widely investigated for its excellent
biocompatibility. Most efforts have been given to improve its low transfection
efficiency. In this study, chitosan was first modified with octaarginine, one of cell
membrane penetrating peptides, and showed enhanced transfection activity, but which
was not significant as expected. Following that, low molecular weight
polyethyleminine (PEI) was introduced to modify chitosan through bioreducible
disulfide linkage, denoted as Chitosan-ss-PEI. PEI is an efficient non-viral vector but
hampered by molecular-weight dependent toxicity. The developed Chitosan-ss-PEI
showed good biocompatibility in MTT assay in three different cell lines, during which
cells were maintained 80% of viability when the concentration of this vector was up
to 100 μg/mL. The optimal transfection efficiency of Chitosan-ss-PEI was higher than
that of PEI 25k and comparable to Lipofectamine in delivering luciferase reporter
gene. GFP expression mediated by Chitosan-ss-PEI also showed similar results.
Chitosan-ss-PEI was then applied to deliver BMP2 gene to skeletal system cells
and exhibited the osteogenic ability. For C2C12 myoblast cells, this system inhibited
their myoblast differentiation and induced the osteogenic differentiation. It also
showed stronger effect in promoting the differentiation of immature osteblast-like
MG63 cells and in inducing C3H10T1/2 mesenchymal stem cells osteogenic
differentiation in term of ALP activity and mineralization ability compared with other
commercial available non-viral vectors. Primary MSCs such as bone marrow stromal
cells (BMSC) and human umbilical cord blood mesenchymal stem cells
(hUCB-MSC), are usually more difficult to transfect, but they showed stronger
osteogenic differentiation ability induced by this system comparing with the cell lines.
BMP2 usually requires extremely high concentration to realize its function.
Through the investigation of BMP2 signaling regulation in this study, it was found
that parathyroid hormone (PTH) could increase the access of BMP2 ligands to their
receptors by negatively influencing BMPs antagonist network, resulted in enhanced
BMP2 activity in bone remodeling and in promoting the commitment of MSC to
osteoblast lineage both in vitro and in vivo. This course involved the endocytosis of
PTHR with a complex of LRP6, which organized antagonist network on the cell
surface to shield the BMPs receptors. Novel approaches are expected to be developed
based on this mechanism with the purpose of intensifying the therapeutic effect of
BMPs.published_or_final_version
Orthopaedics and Traumatology
Doctoral
Doctor of Philosophy
39
Lewis, Christopher John. "The role of bone morphogenetic protein signalling in the control of skin repair after wounding : cellular and molecular mechanisms of cutaneous wound healing mediated by bone morphogenetic proteins and their antagonist Noggin." Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/7337.
Full textAbstract:
Bone morphogenetic proteins (BMPs) and their receptors (BMPRs) coordinate tissue development and postnatal remodelling by regulating proliferation, differentiation and apoptosis. However, their role in wound healing remains unclear. To study this, transgenic mice overexpressing Smad1 (K14-caSmad1) or the BMP antagonist Noggin (K14-Noggin) were utilised, together with human and mouse ex vivo wound healing models and in vitro keratinocyte culture. In wild-type mice, transcripts for Bmpr-1A, Bmpr-II, Bmp ligands and Smad proteins were decreased following tissue injury, whilst Bmpr-1B expression was up-regulated. Furthermore, immunohistochemistry revealed a down-regulation of BMPR-1A in hair follicles adjacent to the wound in murine skin, whilst in murine and human wounds, BMPR-1B and phospho-Smad-1/5/8 expression was pronounced in the wound epithelial tongue. K14-caSmad1 mice displayed retarded wound healing, associated with reduced keratinocyte proliferation and increased apoptosis, whilst K14-Noggin mice exhibited accelerated wound healing. Furthermore, microarray analysis of K14-caSmad1 epidermis revealed decreased expression of distinct cytoskeletal and cell motility-associated genes including wound-associated keratins (Krt16, Krt17) and Myo5a versus controls. Human and mouse keratinocyte proliferation and migration were suppressed by BMP-4/7 both in vitro and ex vivo, whilst they were stimulated by Noggin. Additionally, K14-caSmad1 keratinocytes showed retarded migration compared to controls when studied in vitro. Furthermore, Bmpr-1B silencing accelerated migration and was associated with increased expression of Krt16, Krt17 and Myo5a versus controls. Thus, this study demonstrates that BMPs inhibit proliferation, migration and cytoskeletal re-organization in epidermal keratinocytes during wound healing, and raises a possibility that BMP antagonists may be used for the future management of chronic wounds.
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Lewis, Christopher J. "The role of bone morphogenetic protein signalling in the control of skin repair after wounding. Cellular and molecular mechanisms of cutaneous wound healing mediated by bone morphogenetic proteins and their antagonist Noggin." Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/7337.
Full textAbstract:
Bone morphogenetic proteins (BMPs) and their receptors (BMPRs) coordinate tissue development and postnatal remodelling by regulating proliferation, differentiation and apoptosis. However, their role in wound healing remains unclear. To study this, transgenic mice overexpressing Smad1 (K14-caSmad1) or the BMP antagonist Noggin (K14-Noggin) were utilised, together with human and mouse ex vivo wound healing models and in vitro keratinocyte culture.
In wild-type mice, transcripts for Bmpr-1A, Bmpr-II, Bmp ligands and Smad proteins were decreased following tissue injury, whilst Bmpr-1B expression was up-regulated. Furthermore, immunohistochemistry revealed a down-regulation of BMPR-1A in hair follicles adjacent to the wound in murine skin, whilst in murine and human wounds, BMPR-1B and phospho-Smad-1/5/8 expression was pronounced in the wound epithelial tongue.
K14-caSmad1 mice displayed retarded wound healing, associated with reduced keratinocyte proliferation and increased apoptosis, whilst K14-Noggin mice exhibited accelerated wound healing. Furthermore, microarray analysis of K14-caSmad1 epidermis revealed decreased expression of distinct cytoskeletal and cell motility-associated genes including wound-associated keratins (Krt16, Krt17) and Myo5a versus controls.
Human and mouse keratinocyte proliferation and migration were suppressed by BMP-4/7 both in vitro and ex vivo, whilst they were stimulated by Noggin. Additionally, K14-caSmad1 keratinocytes showed retarded migration compared to controls when studied in vitro. Furthermore, Bmpr-1B silencing accelerated migration and was associated with increased expression of Krt16, Krt17 and Myo5a versus controls.
Thus, this study demonstrates that BMPs inhibit proliferation, migration and cytoskeletal re-organization in epidermal keratinocytes during wound healing, and raises a possibility that BMP antagonists may be used for the future management of chronic wounds.
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Chang, Hsun-Ming. "The roles of oocyte- and theca cell-derived bone morphogenetic proteins in human granulosa cells." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/50685.
Full textAbstract:
Exerting a broad range of biological effects in various tissues, bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor β superfamily. Accumulating evidence indicates that ovarian BMPs are critical regulators of ovarian function and play important roles in the female reproductive system. Mutual communication between oocytes and the surrounding somatic cells is mandatory for normal follicle development, as these locally expressed growth factors function mainly as paracrine/autocrine effectors in granulosa cells.
Previous studies have shown that oocytes may secrete an anti-luteinization factor and theca cells may have luteinization-inhibiting activities. We therefore hypothesized that during the late follicular stage, oocyte-derived and theca cell-derived BMPs may prevent premature luteinization by down-regulating several ovulation-related genes. This study aims to investigate the anti-luteinization effects of oocyte- and theca cell-derived BMPs in human granulosa cells. An established immortalized human granulosa cell line (SVOG), granulosa cell tumor cell line (KGN) and primary granulosa-lutein cells were used as study models. Several parameters of luteinization were investigated following exposure to recombinant human BMP4, BMP7 or BMP15. Dual pharmacological and siRNA-based approaches were used to examine the underlying mechanisms and verify the specificity of the effects.
Our studies demonstrate that oocyte-derived BMP15 functions as a paracrine factor to decrease progesterone production and that theca cell-derived BMP4 and BMP7 down-regulate PTX3 expression in human granulosa cells. In addition, all three growth factors decrease intercellular communication by down-regulating Cx43-coupled gap junction formation. Furthermore, both BMP4 and BMP7 increase the production of a luteinization inhibitor activin A by up-regulating the expression of inhibin βA subunit and furin. Interestingly, different BMPs act through differential subsets of type I receptor-driven SMAD-dependent pathways. These results suggest that oocytes and theca cells may play important roles in the prevention of premature luteinization, a process that is essential for normal ovarian function and fertility. Our findings provide important insight into ovarian biology, and may lead to the development of novel therapeutic tools for fertility regulation.Medicine, Faculty of
Obstetrics and Gynaecology, Department of
Graduate
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Harrington, A. E. "Structural and functional analyses of follistatin, a secreted antagonist of activins and bone morphogenetic proteins." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603738.
Full textAbstract:
Follistatin is a secreted glycoprotein that binds to and prevents the activation of cell surface receptors by growth factors of the TGF-β superfamily. It is composed of four disulfide-rich domains, three of which adopt the follistatin (FS) domain fold. A region in the Fs1 domain, rich in basic residues, is responsible for the protein’s interaction with heparin sulfates (HS) in the extracellular milieu. The nature of this association is investigated in this work by various biophysical studies, which, inter alia, demonstrate that HS and analogues with greater than six disaccharide units are capable of binding two Fs1 domains. This may facilitate the inhibition of dimers of activin and related proteins, by enabling two molecules of follistatin to co-localise adjacent to herparan sulphate glycosaminoglycans. In addition to these studies, the nature of the activin-binding activity of follistatin is explored, and it is revealed to residue in no one domain of the protein. However, a construct of follistatin corresponding to the first two FS domains is shown to be capable of activin binding, and a complex of this Fs12 fragment bound to human activin A has been crystallised. The X-ray crystal structure has been solved by molecular replacement methods to a resolution of 2.6 Å, and reveals in detail the key determinants of activin binding by follistatin. Ultimately, this work enhances our understanding of the mode of action of follistatin, and may illuminate research on its crucial role in the early embryonic development of Xenopus laevis.
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Li, Jin. "Bone morphogenetic proteins and their co-receptor, repulsive guidance molecules, signalling pathways in human cancers." Thesis, Cardiff University, 2010. http://orca.cf.ac.uk/55075/.
Full textAbstract:
RGMs (repulsive guidance molecules) are a group of recently identified GPI (glycosylphosphatidylinositol)-linked cell-membrane-associated proteins, comprising three family members, which have been implicated in BMPs (Bone morphogenetic proteins) signalling. BMPs have been shown to play profound roles in bone metastases from breast cancer and prostate cancer. This study aims to investigate the implication of RGMs in prostate cancer and breast cancer and their role in coordinating signal transduction by BMPs during disease progression of cancer. The aberrant expression of RGMs was found in breast cancer which was associated with prognosis of breast cancer patients. RGMA, B and C were detected in prostate cancer cell lines and only RGMB was expressed in breast cancer cell lines which allowed for the knockdown study of RGMs in PC-3 and RGMB in MDA-MB-231 using ribozyme transgenes. The knockdown of RGMB in breast cancer cells resulted in an increase of cellular proliferation, adhesion, motility and migration in vitro, which contributed to a tumour's growth and metastasis. Furthermore, an inhibition of caspase-3 was seen in cells after knockdown of RGMB which indicated RGMB as a regulator of cell survival. Up-regulation of FAK and Paxillin were also seen in the cancer cells after loss of RGMB expression, together with an evident induction of EMT (epithelial-mesenchymal transition) which may contribute to the promoted cell-matrix adhesion and cell mobility. The knockdown of RGMs in prostate cancer cells also lead to an increase of cell ability to grow, adhere and move, in which differentiated response of ID-1, a BMPs target gene was seen. As RGMs were reported to be involved in BMP signalling, knockdown of RGMB was found to induce promotion on Smad-dependent pathways (especially Smad-1/5/8 pathway) and inhibition on BMP Smad-independent pathways (MAPK JNK pathway). It suggests that RGMs are important partners to fine-tune responses of cells to BMPs stimuli, particularly during the progression and dissemination of cancer cells, and are potential targets for developing a novel cancer therapy.
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Faure, Marie-Odile. "Bone morphogenetic proteins (BMPs) : new modulators of the follicle stimulating hormone (FSH) synthesis and release." Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/30189.
Full textAbstract:
To extend our knowledge on FSH synthesis regulation, we investigated the potential role of BMPs in the ewe pituitary. The two types of BMP receptors (BMPR-IA and BMPR-II) co-localised with gonadotrope cells and their ligands (BMP-2, BMP-4, BMP-7 and GDF-9) mRNAs were detected in the pituitary suggesting a paracrine action of BMPs. BMPR-IB \was not detected on gonadotropes. Interestingly, in three breeds of ewes, BMP-4 as well as BMP-6, BMP-15 and GDF-9 inhibited specifically the FSH synthesis and release, but not the LH production from ewe pituitary cells. Moreover, BMP-4 antagonized the stimulatory effect of activin and amplified the inhibitory action of 17β-estadiol. To determine at which level BMP-4 was able to act on FSH differential secretion, we investigated the Smads signalling pathways. BMP-4 activated the phosphorylation of Smad-1/5 without affecting Smad-2 phosphorylation level triggered by activin. The blockade by inhibitory Smad, Smat7 showed the role of the Smad signalling in BKP-4 action. Blocking the activin signalling by follistatin suggested independence between activin and BMP-4 signalling pathways. In the mouse gonadotrope cell line (LβT2), BMPs and their receptors mRNAs were detected. In contrast to ewe, BMP-4 alone was not able to modulate the gonadotropin secretion. However, BMP-4 amplified the stimulatory effect of activin and GnRH on FSH secretion. Moreover, BMP-4 inhibited the stimulatory effect of activin and GnRH on LH production by inhibiting the expression of GnRH receptor. These differences of effect due to the species underlined the necessity of studying different models to enhance our understanding of reproductive function.
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Luvizuto, Eloá Rodrigues [UNESP]. "O efeito da BMP-2 sobre as propriedades osteocondutoras do beta-tricálcio fosfato em defeitos de calvária de ratos." Universidade Estadual Paulista (UNESP), 2011. http://hdl.handle.net/11449/101204.
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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
A neoformação óssea em defeitos críticos em calvária de ratos depende fortemente das propriedades osteocondutoras dos enxertos e biomateriais. Ainda é controverso se os biomateriais podem substituir os enxertos de osso autógeno e se a suplementação dos biomateriais com Proteínas Ósseas Morfogenéticas (BMPs) é necessária para melhorar a formação óssea. Examinamos defeitos críticos em calvária de ratos (5 mm de diâmetro) tratados com β-tricálcio fosfato (TCP; Cerasorb ® M), gel de ácido polilático e poliglicólico (PLA/PGA; Fisiograft®) e cimento de fosfato de cálcio (CPC; Norian® CRS®), isoladamente ou na presença de 5μg de BMP-2 após 45 dias. Defeitos tratados com enxerto de osso autógeno particulado e defeitos não tratados serviram como controle. A formação óssea foi avaliada com base na análise de μCT, análise histomorfométrica e análise de fluorescência. Nós relatamos que o TCP apoia a formação óssea de forma mais eficiente do que o enxerto de osso autógeno particulado. A formação óssea na presença de TCP sozinho atingiu um nível máximo de neoformação óssea, enquanto que a suplementação de BMP-2 falhou em melhorar a neoformação óssea. Em contrapartida, não houve diferença significativa na formação óssea quando o PLA / PGA e o CPC foram comparados ao enxerto autógeno. Além disso, a presença de BMP-2 não alterou substancialmente as propriedades osteocondutoras de PLA/PGA ou de CPC. Conclui-se que as propriedades osteocondutoras do TCP são superiores aos dos enxertos autógenos e que o TCP não exige suplementação de BMP-2. Nossos resultados também mostram que a diminuição da capacidade osteocondutora do PLA/PGA e do CPC não podem ser superadas pela suplementação de BMP-2 em defeitos de calvária de ratos
Bone formation in critical-sized calvaria defects is strongly dependent on the osteoconductive properties of grafts. It remains a matter of controversy whether biomaterials can replace autografts and whether the supplementation of biomaterials with Bone Morphogenetic Proteins (BMPs) is necessary to enhance bone formation. We examined rat calvaria critical-sized defects (5mm diameter) treated with β-tricalcium phosphate (TCP; Cerasorb® M), polylactic and polyglycolic acid gel (PLA/PGA; Fisiograft®) and calcium phosphate cement (CPC; Norian® CRS®), either alone or in the presence of 5μg of BMP-2 after 45 days. Autografts and untreated defects served as controls. Bone formation was evaluated based on μCT analysis, histomorphometric analysis and fluorescence analysis. We report that TCP supported bone formation more efficiently than did autografts. Bone formation in the presence of TCP alone reached a maximal level, as BMP-2 supplementation failed to enhance bone formation. By contrast, no significant difference in bone formation was observed when PLA/PGA and CPC were compared to autografts. Moreover, the presence of BMP-2 did not substantially change the osteoconductive properties of PLA/PGA or CPC. We conclude that the osteoconductive properties of TCP are superior to those of autografts and that TCP does not require BMP-2 supplementation. Our findings also show that the decreased osteoconductive properties of PLA/PGA and CPC cannot be overcome by BMP-2 supplementation in rat calvaria defects
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Schütte, Andrea. "Autoantibodies against growth factors and their receptors in fracture healing." Doctoral thesis, Humboldt-Universität zu Berlin, Lebenswissenschaftliche Fakultät, 2016. http://dx.doi.org/10.18452/17656.
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Die Knochenregeneration während der Frakturheilung beinhaltet das Zusammenspiel von Wachstumsfaktoren. In einigen Patienten kommt es zu einer verzögerten oder unvollständigen Heilung. Die Gründe hierfür sind bisher nicht komplett verstanden. Neutralisierende Autoantikörper (aAB) gegen Wachstumsfaktoren oder deren Rezeptoren könnten den Heilungsprozess verzögern und potentiell beeinträchtigen In dieser Arbeit wurden 265 Frakturpatienten analysiert. Autoantikörper gegen IGF1 Rezeptor, Insulin Rezeptor, BMP7, BMP2, IGF1 und (Pro)Insulin wurden in den Seren dieser Frakturpatienten gemessen. In Frakturpatienten wurden in 5% der Seren aAB gegen den IGF1R und in 6% gegen den IR gefunden. Das Auftreten von IGF1R- und IR-aAB wurde nicht induziert und war nicht mit dem Heilungsergebnis assoziiert. BMP7-aAB wurden in 1-2,5% gesunder Probanden und Frakturpatienten, die nicht mit rhBMP7 behandelt wurden, detektiert. Patienten, die mit rhBMP7 behandelt wurden, zeigten ein höheres Auftreten der BMP7-aAB Positivität mit 6% zum Zeitpunkt der Operation und 18% vier Wochen nach der Operation. BMP2-aAB wurden in 2% der gesunden Kontrollen und 6% der mit rhBMP7-behandelten Frakturpatienten entdeckt. Bei der Charakterisierung des biologischen Effekts der BMP7-aAB durch einen zell-basierten Reporter-Assay, zeigte sich ein neutralisierender Effekt in Proben mit hohem BMP7-aAB Titer. Als das wichtigste Kriterium für klinische Relevanz wurde die Konsolidierung untersucht. Das Vorhandensein von BMP-aAB wurde nicht signifikant mit der Konsolidierung in Zusammenhang gebracht. Zusammenfassend wurden neue diagnostische Assays zur Detektion von aAB gegen Wachstumsfaktoren und deren Rezeptoren generiert und angewandt um aAB in Seren von Frakturpatienten zu messen. Keiner der identifizierten aAB war negativ mit dem Heilungsprozess assoziiert. Bedenken bezüglich der Sicherheit von rhBMP7 Behandlungen sind berechtigt, da die Anwendung aAB gegen BMP7 induziert, die den BMP7-Signalweg blockieren.Regeneration of bone during fracture healing includes concerted actions of growth factors. Some fractures show delayed healing or non-union due to as yet unknown reasons. Neutralizing autoantibodies (aAB) against growth factors or their receptors might influence and potentially impair the bone healing capacity. In this study, a cohort of 265 fracture patients with different treatment regimen and healing outcomes were analysed. Autoantibodies against IGF1 receptor, insulin receptor, BMP7, BMP2, IGF1 and (pro)insulin were measured in sera of these fracture patients. The prevalence of aAB against IGF1R and IR was 5% and 6% in fracture patients, respectively. The appearance of IGF1R- and IR-aAB was not induced by the surgical intervention and was unrelated to the healing outcome. BMP7-aAB were found in 1-2.5% of healthy subjects and in fracture patients that were not treated with rhBMP7. Patients that had received rhBMP7 treatment showed a higher incidence of BMP7-aAB positivity of 6% at surgery and 18% four weeks post surgery. BMP2-aAB were found in 2% of healthy controls and 6% of the fracture patients that were treated with rhBMP7. Characterizing the biological effect of BMP7-aAB in a cell-based reporter assay, a neutralizing effect was observed for samples with high titres. As the most relevant clinical outcome, the criterion consolidation was analysed defining whether the fracture gap was closed after six months or not. The presence of BMP-aAB was not significantly associated with the healing outcome. In summary, novel diagnostic assays for the detection and quantification of growth factor and receptor aAB were generated and used to determine aAB in sera from fracture patients. None of the identified aAB were negatively associated with the regeneration process or healing outcome. Ongoing concerns regarding the safety of rhBMP7 treatment are justified as the biological treatment induces aAB against BMP7 that block the BMP signal transduction.
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Star, Gregory. "The effects of bone morphogenic proteins and transforming growth factor [beta] on in-vitro endothelin-1 production by human pulmonary microvascular endothelial cells /." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111942.
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Introduction: Idiopathic Pulmonary arteriole hypertension (IPAH) is a rare but severely debilitating disease that strikes women to men at a ratio of 3:1. Endothelial cell (EC) dysfunction is a hallmark of the disease. This includes rapid growth of the ECs until the occlusion of the vasculature as well as decreased blood levels of vasodilators. Markedly increased levels of endothelin-1, a potent vasoconstrictor and smooth muscle mitogen, have been noted in IPAH patients.Recently mutations in the bone morphogenic protein receptor type II (BMPRII) have been linked to the disease. Interestingly mutations in activin-like kinase-1 (ALK-1) and endoglin have been linked to hereditary haemorrhagic telangiectasia (HHT), a disease that results in PAH clinically indistinguishable from IPAH. All of these proteins are either receptors or co-receptors to members of the TGFbeta superfamily. The connection of these mutations to the disease still remains largely a mystery to researchers and the effects of either bone morphogenic proteins 2, 4, 7 or TGFbeta levels on endothelin-1(ET-1) production in human microvascular endothelial cells cultured from normal lungs (HMVEC-LBI) are unknown.
Methods: HMVEC-LBI cells were cultured in the presence of various concentrations of BMP 2,4,7 and TGFbeta, in complete media or serum starved conditions. After allotted time points the media was collected and assayed by ELISA, meanwhile the cells were lysed and protein content assayed for normalization purposes. Small Mothers against Decapentaplegic (SMAD) 1/5 phosphorylation was also measured.
Results and Conclusions: Despite evidence that all BMPs used were biologically active, namely through SMAD phosphorylation studies, only BMP7 at very high dosages increased ET-1 production levels. TGFbeta had a more pronounced effect at earlier time points with lower concentrations. The results provide insights on the effects of an important group of proteins, the BMPs and TGFbeta, on lung microvascular ECs and which are likely the key cellular player In IPAH development. These findings may have clinical relevance in terms of control of the disease and understanding the normal response of these cells BMPs and TGFbeta.
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Boulet, Nathalie. "Rôles des Bone Morphogenetic Proteins dans la conversion adipocytaire et le développement du tissu adipeux humain." Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30187/document.
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Les adipocytes (cellules spécialisées dans le stockage des graisses) sont formés à partir de cellules immatures appelées cellules progénitrices lors du processus d'adipogenèse. Chez l'homme, les différentes étapes de ce processus sont mal connues ainsi que les signaux qui le régulent. La première partie de mon travail de thèse a eu pour but de caractériser la cellule intermédiaire entre la cellule progénitrice et l'adipocyte : le préadipocyte. La deuxième partie a consisté à évaluer le rôle des protéines morphogénétiques de l'os (ou BMP), des inducteurs de l'adipogenèse décrits chez la souris, dans l'adipogenèse humaine. Nous avons montré que les BMP2, 4 et 7 sont produites dans le tissu gras humain et BMP7 est modulée par l'obésité. Les BMP2 et 4 induisent l'adipogenèse des cellules progénitrices humaines mais seule la BMP7 permet la production d'adipocytes particuliers " beiges " décrits pour consommer les lipides et produire de la chaleur. Ces travaux affinent nos connaissances sur les mécanismes impliqués dans l'expansion du tissu gras et permettront d'élaborer des stratégies pour lutter contre le développement des pathologies liées à l'obésitéAdipocytes (cells specialized in fat storage) arise from immature cells, called progenitor cells, during the process of adipogenesis. In human, the different stages of adipogenesis are not well defined as well as the signals involved in adipogenic modulation. The first part of my thesis work aimed to characterize the intermediate cell state between progenitor cell and mature adipocyte: the preadipocyte. The second part aimed to evaluate the role of bone morphogenetic proteins (BMPs) in human adipogenesis. In mice, BMP2 and BMP4 induce classical adipogenesis whereas BMP7 leads to the production of "brite" adipocytes with the capacity to use lipids to produce heat. We have shown that BMP2, 4 and 7 are produced in human fat depots and BMP7 is modulated by obesity. BMP2 and 4 induce classical adipogenesis and BMP7 only induces brite adipogenesis from human progenitor cells. These works improve our knowledge about the mechanisms involved in the expansion of fat depot and may allow the identification of new strategies to fight against the development of obesity-associated pathologies
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Zachos, Terri A. "Gene-augmented mesenchymal stem cells in bone repair." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1146076285.
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Whittle, Andrew John. "A role for bone morphogenetic protein 8b in brown adipose tissue thermogenesis and energy homeostasis." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609416.
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