Global ETD Search

11	The role of bone morphogenetic proteins in the development of the vertebrate midbrain Eom, Dae Seok 08 February 2011 (has links) The purpose of the thesis is to explore the role of BMP signaling in developing vertebrate midbrain. BMP signaling plays important roles in various tissues and stages of neural development to regulate cell fate, proliferation, differentiation, morphogenesis and more. We observed that several major BMPs are expressed not only at the roof plate but also the floor plate of the midbrain. This has led us to ask the role of BMP signaling in dorsal and ventral midbrain patterning. Despite ventral experiments, we found that BMP signaling does not regulate ventral cell fate specification in the midbrain. Instead BMPs profoundly influence the shape and early morphogenesis of the midbrain neural plate as it closes into a neural tube. During neural tube closure, one of the early events occurring at the ventral midline is median hinge point (MHP) formation. Failure to form MHP leads to neural tube closure defects, the 2nd most common birth defects in humans. However, the molecular mechanisms underlying MHP formation are not well known. We found that the lowest BMP signaling occurs at the MHP during early neurulation and BMP blockade is necessary and sufficient for MHP formation. Interestingly, we also demonstrated that BMP blockade directs MHP formation by regulating the apicobasal polarity pathway and this regulation may be mediated by biochemical interactions between pSMAD5 and the apical protein, PAR3. Additionally, our time-lapse data suggest that BMP blockade slows cell cycle progression by increasing duration of G1 to S transition and S phase which leads cell nuclei stay at the basal location longer. This mimics basal nuclear migration seen at the MHP where low BMP signaling occurs. Thus, we conclude that BMP signaling regulates neural tube closure via the apicobasal polarity pathway and in a cell cycle dependent manner at the ventral midline. We observed that BMP signaling is necessary and sufficient for the dorsal cell fate specification in a context-dependent manner and ventral BMP signaling affects dorsal cell fates. Taken together, we propose the idea that BMP signaling has distinct roles in different contexts. BMPs regulate tissue morphogenesis in the ventral midbrain and dorsally cell fate specification. / text Noggin Hinge point Apical constriction Basal nuclear migration Endocytosis EEA1 Rab5 PAR3 Lethal giant larva Tight junctions Adherens junctions Interkinetic nuclear migration Midbrain Bone morphogenetic proteins
12	Serum BMP-2, 4, 7 and AHSG in Patients with Heterotopic Ossification Following Arthroplasty Albilia, Jonathan 14 December 2010 (has links) Purpose: To determine whether reduced serum levels of AHSG and elevated levels of BMP-2, 4, 7 are associated with post-arthroplasty HO. Patients: Thirty arthroplasty patients were included, 15 with evidence of peri-articular HO and 15 without (NHO). Methods: Blood samples were collected from all patients ≥ 8 weeks after arthroplasty. Analytes were measured using ELISAs. Mann-Whitney U tests were performed to compare serum analyte concentrations between HO and NHO groups, and between arthroplasty patients and healthy humans. Results: There is no difference in serum concentrations of AHSG, BMP-2, 4, 7 between HO and NHO patients. Arthroplasty patients showed significantly higher BMP-2 and BMP-4 and lower AHSG serum levels compared to healthy humans (p < 0.01). Conclusion: Baseline BMP-2, 4, 7 and AHSG serum levels are not markers of acquired HO. However, elevated baseline levels of BMP- 2, 4 and reduced levels of AHSG appear to be markers of severe inflammatory arthritis. heterotopic ossification BMP AHSG arthritis markers arthroplasty Joint surgery myossitis ossificans Fetuin Temporomandibular Hip Noggin Alpha-2 HS glycoprotein inflammatory 0567
13	Serum BMP-2, 4, 7 and AHSG in Patients with Heterotopic Ossification Following Arthroplasty Albilia, Jonathan 14 December 2010 (has links) Purpose: To determine whether reduced serum levels of AHSG and elevated levels of BMP-2, 4, 7 are associated with post-arthroplasty HO. Patients: Thirty arthroplasty patients were included, 15 with evidence of peri-articular HO and 15 without (NHO). Methods: Blood samples were collected from all patients ≥ 8 weeks after arthroplasty. Analytes were measured using ELISAs. Mann-Whitney U tests were performed to compare serum analyte concentrations between HO and NHO groups, and between arthroplasty patients and healthy humans. Results: There is no difference in serum concentrations of AHSG, BMP-2, 4, 7 between HO and NHO patients. Arthroplasty patients showed significantly higher BMP-2 and BMP-4 and lower AHSG serum levels compared to healthy humans (p < 0.01). Conclusion: Baseline BMP-2, 4, 7 and AHSG serum levels are not markers of acquired HO. However, elevated baseline levels of BMP- 2, 4 and reduced levels of AHSG appear to be markers of severe inflammatory arthritis. heterotopic ossification BMP AHSG arthritis markers arthroplasty Joint surgery myossitis ossificans Fetuin Temporomandibular Hip Noggin Alpha-2 HS glycoprotein inflammatory 0567
14	Role of the bone morphogenetic protein signalling in skin carcinogenesis. Effect of transgenic overexpression of BMP antognist Noggin on skin tumour development; molecular mechanisms underlying tumour suppressive role of the BMP signalling in skin. Mardaryev, Andrei N. January 2009 (has links) Bone morphogenetic protein (BMP) signalling plays key roles in skin development and also possesses a potent anti-tumour activity in postnatal skin. To study mechanisms of the tumour-suppressive role of BMPs in the skin, a transgenic (TG) mouse model was utilized, in which a transgenic expression of the BMP antagonist Noggin was targeted to the epidermis and hair follicles (HFs) via Keratin 14 promoter. K14-Noggin mice developed spontaneous HF-derived tumours, which resembled human trichofolliculoma. Initiation of the tumours was associated with a marked increase in cell proliferation and an expansion of the hair follicle stem/early progenitor cells. In addition, the TG mice showed hyperplastic changes in the sebaceous glands and the interfollicular epidermis. The epidermal hyperplasia was associated with an increase in the susceptibility to chemically-induced carcinogenesis and earlier malignant transformation of chemically-induced papillomas. Global gene expression profiling revealed that development of the trichofolliculomas was associated with an increase in the expression of the components of several pro-oncogenic signalling pathways (Wnt, Shh, PDGF, Ras, etc.). Specifically, expression of the Wnt ligands and (¿-catenin/Lef1 markedly increased at the initiation stage of tumour formation. In contrast, expression of components of the Shh pathway was markedly increased in the fully developed tumours, compared to the tumour placodes. Pharmacological treatment of the TG mice with the Wnt and Shh antagonists resulted in the stage-dependent inhibition of the tumour initiation and progression, respectively. Further studies revealed that BMP signalling antagonizes the activity of the Wnt and Shh pathways via distinct mechanisms, which include direct regulation of the expression of the tumour suppressor Wnt inhibitory factor 1 (Wif1) and indirect effects on the Shh expression. Thus, tumour suppressor activity of the BMPs in skin epithelium depends on the local concentrations of Noggin and is mediated, at least in part, via stage-dependent antagonizing of the Wnt and Shh signalling pathways. / University of Bradford, NIH and BBSRC. skin carcinogenesis Human skin tumour development Noggin, BMP antognist Signalling Anti-tumour activity Skin hair follicle cancer Wnt Shh Wif1
15	Cell type-dependent differential activation of ERK by oncogenic KRAS or BRAF in the mouse intestinal epithelium Brandt, Raphael 10 March 2023 (has links) Kolorektale Karzinome (CRC) zeigen eine heterogene Ätiologie. Die Progression prämaligner Vorläufer zu CRC unterscheidet (U) sich in Morphologie, molekularen Veränderungen und Interaktion mit der Tumorumgebung. CRC weisen oft onkogene Mutationen in KRAS und BRAF auf. Diese steigern die MAPK Signalwegaktivität (Mpa). Obwohl sie im selben Signalweg wirken, sind KRAS und BRAF auf die CRC-Entitäten U verteilt. Dabei ist KRAS häufiger im sogenannten konventionellen und BRAF im serratierten Weg zu CRC mutiert. In dieser Studie nutzte ich murine intestinale Organoide (iO), die induzierbare (Ind) KRAS oder BRAF Onkogene exprimieren. Große U zwischen KRAS und BRAF zeigten sich sowohl in Signaltransduktion (ST) als auch im Phänotyp. Phosphoprotein-, ERK-Reporter-, scRNA-Seq und EM-Analysen ergaben eine starke Mpa durch BRAF, die zu hoher Expression von MAPK-Zielgenen und Verlust der epithelialen Integrität führte. iO nach KRAS-Ind blieben intakt, korrelierend mit moderater, zelltypspezifischer (ZS) Mpa in sekretorischen und undifferenzierten Zellen. Die meisten Enterozyten waren Mpa-negativ. ERK-Reporter zeigten: Das ZS Muster der Mpa ist nicht nur gegenüber KRAS, sondern auch dem Entzug von Wachstumsfaktoren stabil. Dies spricht für eine intrinsische, robuste Regulierung der Mpa. BRAF-Ind Mpa setzte die ZS Regulierung der MAPK außer Kraft und schädigte das Gewebe, im Einklang mit einer oberen Grenze tolerabler Mpa. Die ZS Mpa wurde in CRC-Zelllinien bestätigt, deren Mpa durch KRAS aber nicht BRAF U ausfiel. Ferner, nutzte ich iO mit bCatenin+KRAS-Ind, um den konventionellen Weg zu CRC zu modellieren. Die Kombination führte zu synergistischen Effekten, die sich in EGFR-unabhängigem Wachstum und der Aufhebung der ZS Mpa-Blockade äußerten, die durch eine Verschiebung der Differenzierung zu mehr Progenitorzellen bewirkt wurde. Zusammenfassend konnte ich U in der Mpa durch KRAS oder BRAF im Darmepithel feststellen, was dazu beiträgt, deren Rollen in der CRC-Genese zu bestimmen. / Colorectal cancer (CRC) is a disease with heterogeneous etiology. Premalignant lesions follow distinct routes of progression to carcinoma reflected by differences in morphology, molecular alterations and the tumor environment. Mutant KRAS and BRAF are frequent, leading to MAPK pathway activation (Mpa), which is relevant for CRC therapy. Despite acting in the same pathway, mutant KRAS and BRAF segregate to different entities, as KRAS is more frequent in the conventional- and BRAF being specific for the serrated route to CRC. I used murine intestinal organoids (iO) expressing inducible oncogenic KRAS or BRAF to study the impact of oncogenes in primary cells. I found marked differences in signal transduction and phenotype. Phospho-protein, ERK-reporter, scRNA-seq and EM data showed strong Mpa upon BRAF induction followed by ERK-target gene expression leading to tissue disruption. In contrast, KRAS left the tissue intact resulting in less and cell type-dependent Mpa limited to secretory cells, a subset of late-stage enterocytes and undifferentiated crypt cells. Most enterocytes were irresponsive to KRAS. The pattern of Mpa was robust towards KRAS or growth factor depletion arguing in favor of intrinsic, resilient MAPK regulation. In iO, BRAF-induced Mpa could break this cell type-specific regulation, indicating an upper limit of tolerable Mpa. I validated these findings in CRC cell lines that differed in Mpa in response to oncogenic KRAS but not BRAF. Finally, I used iO expressing an inducible form of stabilized bCatenin in combination with KRAS to mimic events frequently found in the conventional pathway to CRC. Expression of KRAS and bCatenin synergized in driving EGFR independent growth and breaking the villus-specific block of Mpa by altering differentiation towards progenitor cell types. In summary, this study emphasizes differences between Mpa induced by oncogenic KRAS or BRAF which helps clarifying their nature in different etiological routes to CRC genesis. KRAS KRASG12V BRAF BRAFV600E EGFR EGF MAPK ERK FIRE Reporter MEK MAPKK MAPKKK beta-Catenin intestinale Organoidkultur intestinale Organoide Mausmodelle von Tumoren kolorektales Karzinom kolorektale Karzionome CRC Primärzellen Tumormodelle Onkogene oncogenes KRAS oncogenes BRAF onkogene Signaltransduktion 3D Modell matrigel R-spondin RSPO Noggin KRAS KRASG12V BRAF BRAFV600E EGFR EGF MAPK ERK FIRE reporter MEK MAPKK MAPKKK beta-Catenin intestinal organoid intestinal organoids intestinal organoid culture murine model of cancer colorectal carcinoma CRC primary tumor model oncogenes oncogenic KRAS oncogenic BRAF 3D model matrigel R-spondin RSPO Noggin 610 Medizin und Gesundheit ddc:610
16	Extracellular Matrix Based Materials for Tissue Engineering Aulin, Cecilia January 2010 (has links) The extracellular matrix is (ECM) is a network of large, structural proteins and polysaccharides, important for cellular behavior, tissue development and maintenance. Present thesis describes work exploring ECM as scaffolds for tissue engineering by manipulating cells cultured in vitro or by influencing ECM expression in vivo. By culturing cells on polymer meshes under dynamic culture conditions, deposition of a complex ECM could be achieved, but with low yields. Since the major part of synthesized ECM diffused into the medium the rate limiting step of deposition was investigated. This quantitative analysis showed that the real rate limiting factor is the low proportion of new proteins which are deposited as functional ECM. It is suggested that cells are pre-embedded in for example collagen gels to increase the steric retention and hence functional deposition. The possibility to induce endogenous ECM formation and tissue regeneration by implantation of growth factors in a carrier material was investigated. Bone morphogenetic protein-2 (BMP-2) is a growth factor known to be involved in growth and differentiation of bone and cartilage tissue. The BMP-2 processing and secretion was examined in two cell systems representing endochondral (chondrocytes) and intramembranous (mesenchymal stem cells) bone formation. It was discovered that chondrocytes are more efficient in producing BMP-2 compared to MSC. The role of the antagonist noggin was also investigated and was found to affect the stability of BMP-2 and modulate its effect. Finally, an injectable gel of the ECM component hyaluronan has been evaluated as delivery vehicle in cartilage regeneration. The hyaluronan hydrogel system showed promising results as a versatile biomaterial for cartilage regeneration, could easily be placed intraarticulary and can be used for both cell based and cell free therapies. Extracellular matrix collagen synthesis bioreactor cell culture bone morphogenetic protein-2 noggin hyaluronan cartilage Medical technology Medicinsk teknik Molecular biology Molekylärbiologi Orthopaedics Ortopedi Transplantation surgery Transplantationskirurgi Biomaterials Biomaterial Morphology, cell biology, pathology Morfologi, cellbiologi, patologi Cell and molecular biology Cell- och molekylärbiologi Polymer chemistry Polymerkemi Materials chemistry Materialkemi

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