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Tesi sul tema "Epidermolysis bullosa"

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Autore: Grafiati

Pubblicato: 4 giugno 2021

Ultima modifica: 9 marzo 2023

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1

Kemp, Matthew W. St George Clinical School UNSW. "Gene studies in epidermolysis bullosa". Awarded by:University of New South Wales. St. George Clinical School, 2005. http://handle.unsw.edu.au/1959.4/23439.

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Epidermolysis bullosa (EB) is a group of inherited blistering diseases that share the common feature of blister formation subsequent to normal mechanical insult of the epidermis. Despite two decades of investigation at both epidemiological and genetic levels, there remains much yet to be uncovered about the pathophysiology of this disease. This research had dual aims. Firstly, by enrolling patients in Australia and New Zealand with the simplex type of EB (EBS) in a screening programme in conjunction with a highly detailed review of the EB and intermediate filament literatures, we hoped to gain a better understanding of the correlation between genotype and phenotype in EBS. Secondly, we attempted to evaluate the use of baculoviral vectors as a means of introducing the type VII collagen cDNA into human dermal fibroblasts and primary human epidermal keratinocytes. Among the EBS patients screened we identified a novel multi residue deletion in keratin 5 which led to a surprisingly mild form of epidermolysis bullosa Dowling ??? Meara. The quantitative polymerase chain reaction analysis of epidermal tissue from the affected individual showed that the mutant transcript was present at levels 2.7 fold higher than the wild type transcript. We demonstrated a family in which the presence of a previously reported keratin 14 mutation A413T appeared to induce disease expression in only one of the three individuals found to carry the mutations. We also identified two EBS families with no mutations in either keratin 5 or keratin 14. This is the first study to analyse EB patients from New Zealand and the first to report the presence of a deletion mutation in the 2B domain of keratin 5. The results of our type VII collagen transfer work showed that baculoviruses can be engineered to contain insert sequences in excess of 10kb and are able to gain entry to both human dermal fibroblasts and primary human epidermal keratinocytes. Electron microscopy and analyses of the baculoviral vectors showed that the lack of protein expression subsequent to infection of human dermal fibroblasts and primary human epidermal keratinocytes is likely due to the inability of the vector to escape cytoplasmic endosomes.

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2

McKenna, Kevin Eamon. "Molecular analysis of epidermolysis bullosa". Thesis, Queen's University Belfast, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357463.

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3

Winship, Ingrid M. "Epidermolysis bullosa in South Africa". Doctoral thesis, University of Cape Town, 1986. http://hdl.handle.net/11427/25674.

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4

Mallipeddi, Rajeev. "Understanding squamous cell carcinoma in epidermolysis bullosa". Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416097.

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5

Al, Maani Noor Walid Salem. "Refining genotype-phenotype correlation in epidermolysis bullosa". Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/refining-genotypephenotype-correlation-in-epidermolysis-bullosa(0efb4606-e7eb-422c-9402-28c29de6ebfc).html.

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Dystrophic epidermolysis bullosa results from mutations in COL7A1 that encodes collagen VII, the major component of anchoring fibrils. General paradigms have emerged attributing dominant DEB to heterozygous glycine substitutions and recessive DEB to nonsense, frameshift or splice site mutations on both COL7A1 alleles. Several aspects of the genotype-phenotype heterogeneity encountered in DEB remain unexplained, although genetic, epigenetic and environmental modulators have been implicated. In this thesis, various aspects of DEB were studied, in a bid to refine genotype-phenotype correlation. A detailed analysis of missense GS and non-GS mutations identified 57 novel mutations and was in-keeping with the general established paradigms. Unique clinical entities such as EB-pr and BDN were studied. The role of the matrix metalloproteinase-1 promoter polymorphism, -1607 1G/2G, on disease modification in EB-pr was explored, but was shown to be an unlikely modulator. A large study of BDN, highlighted that intracytoplasmic retention of collagen VII and stellate bodies were not exclusive to BDN and can be associated with various subtypes of DEB, non-EB cases and normal skin. The first case of revertant mosaicism in DEB was studied revealing intragenic cross-over as the underlying mechanism. Finally, intradermal injection of allogeneic fibroblasts was shown to result in increased and sustained expression of COL7A1 possibly through the upregulation of HB-EGF. Recognition of disease modifiers in DEB and refinement of genotype–phenotype correlation will not only further our understanding of DEB but will have implications on diagnosis, counselling and prognosis through patient specific and targeted therapy.

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6

Jones, S. M. "The ocular complications in children with epidermolysis bullosa". Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1338582/.

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Abstract (sommario):

Epidermolysis bullosa (EB) describes a group of inherited bullous disorders affecting the basement membrane zone of skin and mucous membranes. It is characterised by fragility and blistering of the skin and mucosa following friction or mechanical trauma. Ocular features are thought to result from a lack of adherence and disruption of the corneal and/or conjunctival epithelium. This thesis aimed to prospectively evaluate the ocular complications occurring in children with EB via comprehensive ocular examination including assessment of the anterior segment, posterior segment and ocular movements. Findings demonstrated the majority of EB patients exhibit signs of meibomian gland dysfunction (MGD) and decreased tear break up time (TBUT), abnormal tear films on Tearscope® evaluation and ocular surface anomalies. Two further cohorts were studied; a) Age-matched control patients with no anterior segment pathology to provide normative data on MGD and TBUT and b) Children diagnosed with MGD who did not suffer from EB to compare the ocular surface phenotype in these, with that in children with EB and MGD. Having identified MGD and an abnormal ocular surface in children with EB, and shown effective management of MGD in otherwise healthy children, translational research was performed to evaluate the effect of potential therapeutic options at a cellular level. Skills in tissue culture and flow cytometry were developed to work with two untransfected conjunctival cell lines (Immortalized Cell Line (IOBA-NHC) and the Wong-Kilbourne derivative of Chang cells) as an in vitro method to investigate the effect of the current therapeutic agents for MGD on the conjunctival epithelial inflammatory response. In conclusion this thesis furthers our understanding of the ocular phenotype in EB subtypes, the aetiology of ocular features and the appropriate management. Findings may allow future therapeutic developments with greater specificity for children with EB.

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7

Petrova, Anastasia. "Towards hES cell-based therapy of epidermolysis bullosa". Thesis, King's College London (University of London), 2012. https://kclpure.kcl.ac.uk/portal/en/theses/towards-hes-cellbased-therapy-of-epidermolysis-bullosa(79901c47-3f09-41be-b737-fab3127af800).html.

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Regenerative medicine offers great hope for therapeutic innovation in many diseases, including those with defective skin, such as the group of inherited blistering skin diseases known as epidermolysis bullosa. The work in this thesis addresses some of the important pre-clinical approaches to generating keratinocytes (the main cell of the outer skin layer, epidermis) from pluripotent stem cells (human embryonic stem cells, hESCs). Undifferentiated hESCs were exposed to a complex microenvironment in organotypic cultures (to mimic conditions for epidermal stem cell development and maintenance); this yielded epidermis-like structures which stained positively for basal keratin 14 and several extracellular matrix molecules, although a stratified epidermis was not produced. To refine the protocol, hESCs were differentiated to an epidermal cell fate in monolayer cultures in vitro prior to subjecting them to organotypic culture. The most efficient technique involved culture of hESCs on native de-cellularized extracellular matrix produced by normal human dermal fibroblasts as a substrate for differentiation. Large epitheliaHike sheets positive for keratin 14 and p63 expression were observed. On subculture, these cells retained their morphological and immunocytochemical characteristics for up to 5 passages and could be successfully cryo-preserved and recovered. Overall, this study explored the potential of pluripotent stem cells as a source of epidermal progenitors, with results that provide proof-of-concept for future cell therapy innovations in defective skin diseases such as epidermolysis bullosa.

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8

Kühl, Tobias Hans-Jürgen [Verfasser], e Leena [Akademischer Betreuer] Bruckner-Tuderman. "Mesenchymal stromal cell therapy for dystrophic epidermolysis bullosa". Freiburg : Universität, 2016. http://d-nb.info/1119452716/34.

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9

MacDonnell, Samuel. "Recreating Epidermolysis Bullosa Simplex in Zebrafish with Transgenesis". Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/38249.

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Epidermolysis Bullosa simplex (EBS) is a rare genetic disorder that is typically inherited in an autosomal dominant fashion and affects approximately 1 out of 20 000 individuals. This disease is caused by mutations in either the KRT14, KRT5 or PLEC genes. These genes code for proteins involved in the formation of the cytoskeleton in basal keratinocytes, which form the basal layer of the epidermis. The cytoskeleton provides structural support to the basal keratinocytes and mutations in these genes cause cytoskeletal malformations, making these cells more susceptible to physical stress. This results in the cells undergoing lysis under trivial mechanical stress and causing the epidermis to detach from the dermis, the layer immediately below the epidermis. This leads to the primary symptom of EBS: the formation of blisters. The goal of this project is to recreate EBS in zebrafish using transgenesis and to create stable mutant transgenic line. In the future, high throughput drug screening will be done on mutant zebrafish embryos to find potential drug candidates that can alleviate the symptoms of EBS. To accomplish this, missense and deletion mutations in zebrafish krt5 cDNA using site-directed mutagenesis were performed. It was previously shown that mice models for this disease die shortly after birth and thus no stable mutant lines were able to be created. To ensure embryo survival and avoid a similar fate, mutant krt5 cDNA was expressed in non-essential tissue, such as the embryonic fin fold using a fin epithelial-specific enhancer named epi. These constructs were injected into one-cell stage zebrafish embryos, which were raised and screened for integration of the construct in their germ cells. While results from injected embryos were promising, mutant transgenic zebrafish did not demonstrate any blistering. In an attempt to induce blistering, mutant zebrafish embryos were placed under various environmental stressors known to worsen the symptoms of EBS. This was not successful. Expression of mutant keratin 5 in the basal epidermis of the entire embryo using the 2.3kb upstream region of the zebrafish krt5 gene to drive expression also did not yield any results. More investigations are needed to determine if it will be possible to use the zebrafish to model EBS.

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10

Smith, Frances J. D. "Studies of the molecular basis of epidermolysis bullosa simplex". Thesis, University of Edinburgh, 1994. http://hdl.handle.net/1842/20795.

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The aim of this project was to investigate the possible mechanisms for intraepidermal blistering. Attention was concentrated on locating mutations in the genes encoding keratins K5 and K14, the putative defective genes, in five families affected by the Weber-Cockayne form of EBS, characterised by blisters predominantly on the hands and feet. In four of the five families examined, single nucleotide substitutions resulting in an amino acid change were identified. In two families, mutations were identified in the central non-helical L12 linker domain, one in keratin 5 and the other in keratin 14. This was surprising as relatively little is known about this region, and it was not considered to be particularly important in keratin filament assembly or network formation. Another mutation has been reported in this region in keratin 14 in a family with EBS-Koebner characterised by moderate and generalised blistering. Although just two residues away from the mutation reported here, the difference in severity of the resulting phenotypes emphasises the contribution of individual residues to the overall functioning of the keratin filament network. In the third family a mutation was identified in the 1A domain of keratin 5, at the carboxy terminal of this domain. In the fourth family a tentative mutation was identified near the centre of the 2B domain of keratin 14. Extensive sequencing of both K5 and K14 DNA from members of the fifth family did not identify any sequencing discrepancies and genetic linkage analysis suggested that the disease phenotype in this family was linked to the type I keratins. It is possible though, that mutations in minor basal cell keratins such as keratin 15, or in a keratin associated protein, could lead to the same clinical phenotype. Keratin mutations have now been identified in another bullous disorder, bullous congenital ichthyosiform erythroderma, in the supra basal keratins K1 and K10.

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11

Vorobyev, Artem [Verfasser]. "Diagnosis and models of epidermolysis bullosa acquisita / Artem Vorobyev". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2017. http://d-nb.info/1126468878/34.

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12

Schlüter, Ulrich. "Zur Frage der Vernarbung bei Epidermolysis bullosa dystrophica : eine vergleichende histologische und immunhistochemische Untersuchung /". Marburg : Görich und Weiershäuser, 2004. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=013209178&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.

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13

Titman, Penelope Susan. "The psychological impact of skin disorders on children and their families". Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270496.

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14

Compton, Sarah. "Developing ex vivo gene therapy for recessive dystrophic epidermolysis bullosa". Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393399.

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15

Wessagowit, Vasarat. "Keratinocyte gene expression profile in recessive dystrophic epidermolysis bullosa wounds". Thesis, King's College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408868.

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16

Abdul, Wahab Alya Omar. "The development of gene therapy for recessive dystrophic epidermolysis bullosa". Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/the-development-of-gene-therapy-for-recessive-dystrophic-epidermolysis-bullosa(4a405332-0065-448f-b62c-4977ca0d8bf0).html.

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Abstract (sommario):

Epidermolysis bullosa (EB) is a group of inherited mechanobullous disorders characterised by trauma induced blistering. One of the most severe subtypes is recessive dystrophic epidermolysis bullosa (RDEB). RDEB is due to loss of function mutations in the gene encoding type VII collagen (COL7A1), one of the main constituents of anchoring fibrils anchoring the basement membrane to the underlying dermis. There is no cure for this devastating condition although promising pre-clinical studies for strategies using genetic correction, protein replacement, cell therapy or drug therapies are underway. Reconstitution of COL7A1 expression in both keratinocyte and fibroblast cell populations has been demonstrated using ex vivo gene therapy and hypothesised to lead to new anchoring fibril formation and amelioration of disease phenotype. Feasibility of this approach had been demonstrated in pre-clinical studies using a retroviral vector, and this work details the development of a phase 1 clinical trial to graft an autologous gene corrected skin equivalent graft. Detailed analysis of a cohort of adult patients with RDEB was performed in order to identify suitable trial candidates. In addition, an alternative strategy using a lentiviral vector encoding codon-optimised COL7A1 developed in order to transduce fibroblasts to be administered intradermally was developed. Expression and secretion of full-length de novo C7 was confirmed, with transduced cells exhibiting increased levels of protein expression despite only modest transduction efficiencies. This work details the journey and obstacles encountered in developing gene therapy clinical trials for RDEB, both through the development of a phase 1 study for an autologous gene corrected skin equivalent graft as well as a phase I study of intradermal autologous gene corrected fibroblasts.

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17

Huilaja, L. (Laura). "Collagen XVII and pathomechanisms of junctional epidermolysis bullosa and gestational pemphigoid". Doctoral thesis, University of Oulu, 2008. http://urn.fi/urn:isbn:9789514287749.

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Abstract Transmembrane collagen XVII (BP180) is a structural component of hemidesmosomes that connects the two layers of skin. Collagen XVII is associated with both autoimmune and inherited bullous skin diseases. Mutations in collagen XVII gene cause junctional epidermolysis bullosa, and in the diseases of the pemphigoid group autoantibodies target collagen XVII. In this work, collagen XVII was studied in both junctional epidermolysis bullosa and gestational pemphigoid. Two novel glycine substitution mutations were found in the largest collagenous domain of collagen XVII. Analysis of recombinantly produced mutated proteins showed that these novel mutations and previously described glycine substitution mutations decrease the thermal stability of collagen XVII ectodomain. In addition, these mutations were found to cause intracellular accumulation of the mutated proteins and affect the post-translational modifications of collagen XVII. Meanwhile, an in-frame deletion of nine amino acids had no effect on the thermal stability or secretion of the collagen XVII ectodomain. Gestational pemphigoid autoantigen collagen XVII has been mainly studied in the skin, and its expression and function during pregnancy are so far largely unknown. For the first time, collagen XVII was shown to be expressed by cytotrophoblasts of the first trimester human placenta and by cultured cytotrophoblasts. Transmigration assay of cytotrophoblasts indicated that collagen XVII promotes trophoblast invasion, and may thus have a role in placental formation. In addition, significant amounts of in vivo produced collagen XVII were found in the amniotic fluid throughout pregnancy. Collagen XVII expression was also observed in hemidesmosomes of amniotic membranes and in cells cultured from amniotic fluid. These findings suggest that collagen XVII could have a function, albeit so far unknown, during pregnancy.

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18

Horn, Helen M. "The prevalence, clinical features and genetics of epidermolysis bullosa in Scotland". Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/24711.

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Between May 1992 and June 2001, 309 epidermolysis bullosa (EB) sufferers were identified in Scotland (EB simplex [EBS] 175, dystrophic EB [DEB] 130, junctional EB [JEB] 4). The point prevalences of EB per million in June 2001 were: EBS (all variants) 33.2, the Dowling-Meara subtype of EBS (EBS-DM) 1.2, JEB 0.3, DEB (all subtypes) 24.6, dominant DEB ( DDEB) 17.4, DEB of uncertain inheritance (DEB-unc) 4.6, the Hallopeau-Siemens subtype of recessively inherited DEB (RDEB-HS) 1,4, localised RDEB (RDEB-loc) 1.0, and the inverse pattern of RDEB (RDEB-inv) 0.2. Incidences per million live births were EBS (all subtypes) 34.4, JEB 3.2, and DEB (all subtypes) 26.4. Although the prevalence figures for EBS and DEB are the highest of any yet reported, extrapolation of accurate data for the Lothians suggests that the prevalences of EBS and DEB in Scotland are underestimates. Detailed clinical information on 130 EBS patients revealed considerable overlap between EBS-WC and EBS-Kb. As both phenotypes were frequently seen within the same pedigree and in patients bearing identical mutations, EBS-WC is best regarded as a mild variant of EBS-Kb rather than as a separate disorder. Improvement with age was common in EBS but not invariable. Nail involvement and aplasia cutis congentia were seen in all subtypes of EBS. Seasonal variation was confirmed as being common in EBS-Kb/EBS-WC and absent in EBS-DM. In contrast to previously held views, substantial minorities of those with EBS-Kb/EBS-WC experienced oral blisters (17%) and blisters at sites in addition to the palms and soles (43%). Oral blisters were previously thought to occur only in EBS-DM. Laryngeal involvement, usually associated with JEB, also occurred in EBS-DM.

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19

Petrof, Gampriela. "Allogeneic cell-based therapies for individuals with recessive dystrophic epidermolysis bullosa". Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/allogeneic-cellbased-therapies-for-individuals-with-recessive-dystrophic-epidermolysis-bullosa(7e30bed8-6252-45b4-b5f3-cbe70b6a8d81).html.

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Abstract (sommario):

Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of inherited blistering skin diseases that affect 500,000 individuals worldwide. The clinically more severe recessive dystrophic (RDEB) variant affects ~5% of EB individuals with a prevalence of 8 per one million of the population. RDEB is caused by loss-of-function mutations in the type VII collagen gene, COL7A1, which leads to reduced or absent type VII collagen (C7) and structurally defective anchoring fibrils at the dermo-epidermal junction (DEJ). From a clinical perspective, individuals with RDEB have fragile skin and are susceptible to blistering following minimal trauma, which leads to poor wound healing, scarring, contractures and oesophageal strictures. The major cause of mortality in RDEB is metastatic cutaneous squamous cell carcinoma (SCC). At present, care is mainly supportive and there are no effective treatments for this debilitating disease. The main therapeutic challenge, therefore has been to develop gene, protein, cell and drug therapies that are safe, effective and affordable. The basis of this thesis is to evaluate safety and efficacy of allogeneic cell-based therapies and attempt to elucidate their mechanism of action in wound healing in RDEB. To examine if allogeneic fibroblasts promote healing of chronic wounds in RDEB I intradermally injected allogeneic fibroblasts around the wound margins in an individual with RDEB. I demonstrated that these injections result in Heparin-Binding EGF-like Growth Factor encoding gene (HBEGF) and COL7A1 upregulation followed by C7 production. These led to reduction in wound size by 30% at 8 months post injections. HB-EGF, a member of the EGF family, has been implicated in RDEB-associated SCC. I also assessed whether another growth factor, EGF, which is commercially available for human use and which is related to HB-EGF, could upregulate COL7A1 expression in RDEB epidermal cells. I demonstrated in vitro that 100ng/ml EGF at 90 minutes and 10ng/ml at 15 minutes led to 3-fold and 5-fold COL7A1 upregulation in RDEB keratinocytes and fibroblasts respectively. HB-EGF also led to COL7A1 upregulation in RDB keratinocytes (6-fold) but to a lesser extent in RDEB fibroblasts (2-fold). To evaluate the effects of intradermally injected allogeneic fibroblasts in a larger number of RDEB individuals, I conducted a prospective, randomised, vehicle-controlled, phase II clinical trial. Twenty-six wounds in 11 adults with RDEB were injected. Fourteen wounds received fibroblasts and 12 were injected with vehicle only. I showed that allogeneic fibroblasts are safe and lead to a greater reduction in erosion area compared to vehicle within the first 28 days following treatment with a single set of injections to the wound margins, but not thereafter. Finally, I explored the safety and potential of intravenously administered allogeneic bone marrow-derived mesenchymal stromal cells (BM-MSCs) in children with RDEB in an open-label trial. I showed that the infusions were well-tolerated, with no serious adverse events. Although, there was no increase in C7 deposition, children and their parents reported improved wound healing, reduction in blister numbers and pruritus, increased skin resilience to trauma, and reduced pain during dressing changes. In addition, significant reduction in circulating inflammatory cytokines (IL-10, p < 0.001; IFN-γ, p=0.04 and IL-17A, p=0.03) was observed. Taken together, these data reveal new insights into the mechanisms of action of allogeneic cell-based therapies in RDEB and provide evidence for their efficacy in wound healing and reducing morbidity in the context of clinical trials.

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20

Kasprick, Anika [Verfasser]. "Die Beteiligung von Mastzellen in der Autoimmunerkrankung Epidermolysis bullosa acquisita / Anika Kasprick". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2014. http://d-nb.info/1046712403/34.

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21

McGrath, John Alexander. "Abnormalities of wound healing and basement membrane zone composition in dystrophic epidermolysis bullosa". Thesis, King's College London (University of London), 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343791.

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22

Proudfoot, Laura Erin. "The characterisation of cellular and tissue chronic inflammation in recessive dystrophic epidermolysis bullosa". Thesis, King's College London (University of London), 2015. https://kclpure.kcl.ac.uk/portal/en/theses/the-characterisation-of-cellular-and-tissue-chronic-inflammation-in-recessive-dystrophic-epidermolysis-bullosa(ebd52ed7-020a-48cb-9f75-4110ed7d9117).html.

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Abstract (sommario):

Recessive dystrophic epidermolysis bullosa (RDEB) occurs as a result of loss of function mutations in COL7A1, resulting in reduced/absent collagen VII deposition in the anchoring fibril adhesion structures at the dermal-epidermal junction. The condition is typified by severe trauma-induced blistering and cutaneous erosions from infancy and chronic wounds that progress to early aggressive cutaneous squamous cell carcinomas (SCCs) which are the main cause of death in this patient cohort. Thus far, the RDEB chronic inflammatory environment has not been characterised in detail nor is there any theoretical basis for the targeting of candidate genes or inflammatory biomarkers to reduce chronic inflammation that might halt the inevitable malignant decline. The studies presented herein provide a detailed comparative analysis of RDEB wounded skin and control skin at the transcriptional and immunological levels. The findings presented in this thesis: 1) define baseline gene expression profiles and immunobiology of chronically inflamed RDEB skin and blood; 2) reveal matrix metalloproteinase (MMP) family genes germane to RDEB chronic inflammation; 3) provide a body of data and supportive evidence that targeting interleukin (IL)-17-associated signalling pathways may be therapeutically meaningful for treating RDEB patients with chronic wounds; and 4) generate new insights into the functional relevance of these targets in RDEB wounds and RDEB-SCC. Illumina whole-genome expression microarray was used to define the pattern of differential gene expression in RDEB wounded skin. MMP-11, -2 and -9 were revealed as significantly upregulated in RDEB chronic wounds, with augmented MMP-11 levels disclosed in the sera of an extended RDEB cohort. Detailed immunoprofiling of RDEB skin and blood via fluorescence-activated flow cytometry revealed a significant elevation in the pro-inflammatory and pro-tumourigenic cytokine IL-17A, further supported on serum multiplex analyses and correlating with immunohistochemical labelling of RDEB wound and RDEB-SCC cutaneous sections. IL-17A significantly enhanced RDEB and RDEB-SCC fibroblast migration and MMP inhibition alone was insufficient to inhibit this effect. An in vitro organotypic model system was developed to study the effects of IL-17A and MMP-11 on RDEB keratinocytes, although pre-treatment did not induce keratinocyte migration or curtail cell invasion in the RDEB-SCC co-cultures. Taken together, these data provide rationale for future work to examine the potential utility of anti-IL-17 biologic innovations as a therapy for individuals with RDEB, although more detailed functional pre-clinical studies are still needed.

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23

Sitaru, Cassian. "Pathogenicity of autoantibodies to type VII collagen from patients with epidermolysis bullosa acquisita". Doctoral thesis, [S.l.] : [s.n.], 2002. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-3982.

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Abstract (sommario):

Die Epidermolysis bullosa acquisita (EBA) ist eine subepidermal blasenbildende Autoimmundermatose, die mit Autoantikörpern gegen Typ VII Kollagen, den Hauptbestandteil der Verankerungsfibrillen der dermo-epidermalen Junktionszone (DEJ), assoziert ist. Bislang war jedoch unklar, ob diese Autoantikörper tatsächlich eine Blasenbildung verursachen. In der vorliegenden Arbeit gingen wir dieser Frage unter Verwendung eines Gefrierschnitt-Modells nach. Nach Koinkubation mit Leukozyten gesunder Spender induzierten 14 von 16 EBA-Seren eine subepidermale Spaltbildung, nicht jedoch die Seren von gesunden Freiwilligen. Die Spaltbildung erfolgte im Bereich der Lamina lucida der DEJ und war von der Rekrutierung und Aktivierung neutrophiler Granulozyten, nicht jedoch von der Präsenz mononuklearer Zellen abhängig. Autoantikörper von Patienten, die gegen eine rekombinante Form der NC1-Domäne des Typ VII Kollagens affinitätsaufgereinigt wurden, und der gegen die NC-1-Domäne gerichtete monoklonale Antikörper LH7.2 induzierten ebenfalls eine subepidermale Spaltildung. Dagegen führte die Präadsorption der EBA-Seren mit rekombinantem Typ VII Kollagen zum Verlust des blaseninduzierenden Potentials. Diese Fähigkeit verloren auch durch Pepsinverdau hergestellte F(ab’)2-Fragmente der Patienten-Autoantikörper gegen Typ VII Kollagen. Die Ergebnisse dieser Arbeit zeigen, dass Autoantikörper gegen Typ VII Kollagen eine Fcg-abhängige Entzündung und subepidermale Spaltbildung in Gefrierschnitten humaner Haut hervorrufen
Epidermolysis bullosa acquisita (EBA) is an autoimmune subepidermal blistering disease associated with autoantibodies to type VII collagen, the major constituent of anchoring fibrils. Previous attempts to demonstrate the blister inducing potential of autoantibodies to this protein have failed. To address this question, we used an in vitro model involving cryosections of human skin incubated with patients’ autoantibodies and leukocytes from healthy donors. We show that sera from 14 out of 16 EBA patients, in contrast to sera from healthy controls, induced dermal-epidermal separation in the cryosections. The level of the experimentally induced split localizes to the lamina lucida of the dermal-epidermal junction. Recruitment and activation of neutrophils at the dermal-epidermal junction was necessary for split induction, whereas mononuclear cells were not required. Importantly, patients’ autoantibodies affinity-purified against a recombinant form of the non-collagenous 1 (NC1) domain of type VII collagen retained their blister-inducing capacity, while patients’ IgG that was depleted of reactivity to type VII collagen lost this ability. Monoclonal antibody LH7.2 to the NC1 domain of type VII collagen also induced subepidermal splits in the cryosections; F(ab’)2 fragments of autoantibodies to type VII collagen were not pathogenic. These findings demonstrate the capacity of autoantibodies to type VII collagen to trigger an Fcg-dependent inflammation leading to split formation in cryosections of human skin

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24

Ellebrecht, Christoph Thomas [Verfasser]. "In-vivo-Untersuchung zur Vorhersagbarkeit der Epidermolysis bullosa acquisita im Tiermodell / Christoph Thomas Ellebrecht". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2013. http://d-nb.info/103059578X/34.

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25

Williams, Felicity. "A qualitative study of the experiences of children and young people with Epidermolysis Bullosa". Thesis, University of East London, 2008. http://roar.uel.ac.uk/3667/.

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Abstract (sommario):

Background: Very little literature exists regarding children's experiences of Epidermolysis Bullosa (EB). Existing research indicates that EB can have a negative impact on children's self esteem, quality of life, and social relationships. However most of the research in this area has been undertaken with parents of children with the condition and utilises quantitative methodology, and measures of psychological adjustment. Aim: The present study aimed to explore this hitherto largely neglected population, through the use of qualitative methods to investigate the experiences of young people with EB. Method: 11 young people with EB were selected from one hospital in the UK. Participants were interviewed individually, or with their parents present, according to their expressed preference. Transcripts were analysed using Interpretative Phenomenological Analysis (IPA). Results: Analysis resulted in four superordinate themes, which highlighted different aspects of participants' experiences of living with EB: The Self as Different; Physical Activity and Identity; Dependence and Independence; and Coping. Conclusions: The present study provides a detailed account of young people's experiences of EB and furthers understanding of a little researched area. Participants' accounts have highlighted the importance of providing appropriate psychological and peer support, as well as wider community education and intervention, as part of the holistic treatment of young people with this chronic, painful and visible skin condition. In addition, the present study highlights the extent to which young people with EB can contribute knowledge.

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26

Srinivas, Girish [Verfasser]. "Genome-wide mapping of gene-microbiota interactions in susceptibility to epidermolysis bullosa acquisita / Girish Srinivas". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2013. http://d-nb.info/1045769339/34.

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27

Möckel, Nicole [Verfasser]. "Neue Therapieoptionen des bullösen Pemphigoids und der Epidermolysis bullosa acquisita: Untersuchungen am Gefrierschnittmodell / Nicole Möckel". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2014. http://d-nb.info/1052241867/34.

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28

Marx, Jennifer. "In vitro modelling of recessive dystrophic epidermolysis bullosa (RDEB) using stem cells and genome editing". Thesis, Högskolan i Skövde, Institutionen för hälsa och lärande, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-17333.

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Epidermolysis Bullosa (EB) is a group of inherited skin blistering diseases which is associated with severely compromised integrity of the skin. One of the most severe form is recessive dystrophic EB (RDEB) caused by loss-of-function mutations in the COL7A1 gene, encoding type VII collagen (COL7). Deficiency of COL7 results in skin fragility, leading to severe recurrent trauma-induced blistering of the skin. Currently, there is no effective therapy or cure for RDEB. Several treatment approaches are ongoing, but the lack of representative skin models of the physiology and structure of the skin have limited such studies to date. Here, induced pluripotent stem cell (iPSC) technology was used in conjunction with genome editing on previously derived iPSCs heterozygous for a mutation in COL7A1 gene (carrier RDEB-iPSC or cRDEB-iPSC) to generate isogenic cRDEB-iPSC lines by complete knock-out of the COL7A1 gene. These can be further used for the generation of 3D human skin organoids and modeling disease in vitro. First, successful reprogramming of the cRDEB-iPSC line was validated in vitro by pluripotency and differentiation capacity assays. CRISPR-Cas9 targeted gene knock-out upon ribonucleoprotein (RNP) transfection of cRDEB-iPSCs using two different RNPs yielded at least one potential knock-out of the COL7A1 gene. However, COL7 expression must be further assessed to confirm complete COL7A1 gene knock-out on the wild-type allele. Nonetheless, the project demonstrated the success in combining the novel iPSCs and CRISPR-Cas9 technologies but revealed the complexity and possible complications associated with their application.

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29

Samavedam, Unni Krishna Sri Rama Lingeswar [Verfasser]. "Contribution of cytokines to the pathogenesis of epidermolysis bullosa acquisita / Unni Krishna Sri Rama Lingeswar Samavedam". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2014. http://d-nb.info/104671256X/34.

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30

Ghorbanalipoor, Saeedeh [Verfasser], Ralf J. [Akademischer Betreuer] Ludwig e Rudolf [Gutachter] Manz. "Drug repurposing for epidermolysis bullosa acquisita / Saeedeh Ghorbanalipoor ; Gutachter: Rudolf Manz ; Akademischer Betreuer: Ralf J. Ludwig". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2020. http://d-nb.info/1209091186/34.

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31

Maguire, Claire Merewyn. "Proteoglycans of the dermal-epidermal junction : their role in maintenance of skin integrity and dystrophic epidermolysis bullosa". Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267703.

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32

Pipi, Eleni [Verfasser]. "Receptor-independent anti-inflammatory activities of IgG : investigations using models of epidermolysis bullosa acquisita (EBA) / Eleni Pipi". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2015. http://d-nb.info/1080281118/34.

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33

Banczyk, David Michael [Verfasser]. "Autoantikörper: Induktion durch polyklonal aktivierte T-Zellen und Modulation in der Epidermolysis bullosa acquisita / David Michael Banczyk". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2013. http://d-nb.info/104395323X/34.

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34

Cole, Clare Louise. "Identification of OATP1B3 as a potential therapeutic target in Recessive Dystrophic Epidermolysis Bullosa Associated Squamous Cell Carcinoma". Thesis, University of Dundee, 2011. https://discovery.dundee.ac.uk/en/studentTheses/20729995-be96-4f29-80b8-53da131c6fd8.

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Epidermolysis Bullosa encompasses a group of inherited heterogeneous diseases involving trauma induced blistering of the skin. Recessive Dystrophic Epidermolysis Bullosa (RDEB) is one of the most debilitating variants of the disease and patients are predisposed to developing aggressive cutaneous Squamous Cell Carcinoma (SCC). Unlike SCC in the general population, the primary cause of RDEB associated SCC is not UV-radiation. SCC in RDEB patients has poor prognosis due to a high frequency of recurrence and metastasis. 70% of all severe generalized RDEB patients die from SCC by the age of 45, compared to only 1.25% of all patients with UV-induced SCC in the general population (Fine et al. 2008), making SCC the leading cause of death in these RDEB patients. The aim of this investigation was to identify therapeutic targets for RDEB associated SCC. Global gene expression studies identified 36 candidate genes which were differentially regulated in RDEB SCC (n=4) compared with non-RDEB SCC (n=5) primary keratinocyte cultures. The validation of these genes by qRT-PCR in replicate cultures of RDEB SCC (n=3), non-RDEB SCC (n=3) keratinocytes and normal human keratinocytes as a control, deduced 5 genes to be significantly differentially regulated. Of particular interest, is the over-expression of SLCO1B3 by 6.25 fold in RDEB SCC keratinocytes (p = 0.035). SLCO1B3 encodes the organic anion transporter OATP1B3, which is normally exclusively expressed on the basolateral membrane of hepatocytes. qRT-PCR revealed the mRNA expression level of SLCO1B3 is reduced in RDEB SCC keratinocyte cultures when COL7A1, the causal gene mutated in RDEB, is re-expressed, suggesting that COL7A1 which encodes the Type VII Collagen protein and is secreted into the extracellular matrix, may suppress the transcription of SLCO1B3. Immunofluorescent staining of RDEB SCC keratinocytes and tissue identified OATP1B3 expression, whilst qRT-PCR using mRNA isolated from freshly frozen skin and SCC tissue samples from both RDEB and non-RDEB individuals identified increased SLCO1B3 mRNA expression in RDEB SCC in vivo. Over expression of SLCO1B3 and increased activity of OATP1B3 is associated with breast, colon and pancreatic cancer and is a known transporter of chemotherapeutic agents, such as Methotrexate and Paclitaxel. These observations have led to speculation that, as a transporter over expressed in cancer and capable of introducing drugs into cells, OATP1B3 represents a potential therapeutic target. Preliminary results from a cell viability assay suggest that exposing RDEB SCC cells to Microcystin-LR specifically reduces cell viability in a SLCO1B3 dependent manner. This supports the conclusion that SLCO1B3 represents a viable RDEB SCC specific therapeutic target and provides a pathway which can be exploited to deliver anti-cancer drugs directly to tumour cells whilst reducing the systemic toxicity of these agents.

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35

Armbrust, Mikko Maurizio [Verfasser]. "Untersuchungen zur Signaltransduktion in Granulozyten nach Bindung an Immunkomplexe am Beispiel der Epidermolysis bullosa acquisita / Mikko Maurizio Armbrust". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2019. http://d-nb.info/1175134171/34.

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36

Niebuhr, Markus Arnold [Verfasser]. "Assessment of the T-lymphocyte receptor repertoire in the experimental model of epidermolysis bullosa acquisita / Markus Arnold Niebuhr". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2019. http://d-nb.info/1193100186/34.

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37

Mezger, Markus Torsten [Verfasser], e Rupert [Akademischer Betreuer] Handgretinger. "Entwicklung eines mRNA basierten Transkript Therapieansatzes zur Behandlung der Erkrankung Epidermolysis bullosa / Markus Torsten Mezger ; Betreuer: Rupert Handgretinger". Tübingen : Universitätsbibliothek Tübingen, 2015. http://d-nb.info/1197058060/34.

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38

Scheuber, Jarno Till [Verfasser]. "Die Effekte einer Inhibition der Januskinase 2 in in vitro Modellen der Epidermolysis bullosa acquisita / Jarno Till Scheuber". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2016. http://d-nb.info/1121536360/34.

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39

Mezger, Markus [Verfasser], e Rupert [Akademischer Betreuer] Handgretinger. "Entwicklung eines mRNA basierten Transkript Therapieansatzes zur Behandlung der Erkrankung Epidermolysis bullosa / Markus Torsten Mezger ; Betreuer: Rupert Handgretinger". Tübingen : Universitätsbibliothek Tübingen, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-639388.

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40

Grund, Nikolai Alexander [Verfasser]. "Inhibition des NF-kB-Signalweges durch CEP-18770 im in-vitro Modell von Epidermolysis bullosa acquisita / Nikolai Alexander Grund". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2018. http://d-nb.info/1171364172/34.

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41

Lunz, Andre [Verfasser]. "Untersuchung über den Einfluss verschiedener Leukozytenpopulationen in der Pathogenese des bullösen Pemphigoids und der Epidermolysis bullosa acquisita / Andre Lunz". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2015. http://d-nb.info/1079011587/34.

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42

Turczynski, Sandrine. "Stratégie thérapeutique par saut d’exon pour les épidermolyses bulleuses dystrophiques". Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05T085.

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Abstract (sommario):

Les Epidermolyses Bulleuses Dystrophiques (EBD) sont des génodermatoses rares et sévères transmises sur un mode autosomique récessif (EBDR) ou dominant (EBDD), dues à une perte de l’adhésion dermo-épidermique. Les patients atteints d’EBD souffrent de décollements bulleux cutanéo-muqueux qui menacent le pronostic fonctionnel et vital dans les formes les plus graves. Toutes les formes d’EBD sont dues à des mutations du gène COL7A1 codant pour le collagène VII qui est le constituant des fibres d’ancrage assurant l’adhésion de l’épiderme au derme. Il n’existe actuellement pas de thérapie satisfaisante des EBD. La première partie de ma thèse visait à démontrer la faisabilité d’une approche thérapeutique par saut d’exon des EBDR. Cette stratégie consiste à exciser l’exon porteur de la mutation durant le processus d’épissage, afin de restaurer l’expression d’une protéine fonctionnelle. Les exons 73 et 80 de COL7A1 sont particulièrement intéressants car ils sont le siège de mutations récurrentes et que leur excision préserve le cadre ouvert de lecture. Nous avons dans un premier temps démontré le caractère non indispensable des séquences codées par ces exons in vivo en utilisant un modèle de xénogreffe de peau humaine EBDR reconstruite, génétiquement modifiée à l’aide de vecteurs rétroviraux exprimant l'ADNc de COL7A1 délété des séquences des exons 73 ou 80. Puis, j’ai pu établir que la transfection d’oligoribonucléotides antisens (AONs) dirigés contre certaines séquences régulatrices de l’épissage permettait d’induire le saut en phase de ces exons dans des cellules primaires de patients EBDR, avec une efficacité atteignant 90% de saut d’exon. Les analyses par western blot et immunocytofluorescence après transfection ont permis de mettre en évidence une réexpression significative du collagène VII (jusqu’à 25%) dans les cellules de trois patients EBDR. Enfin, j’ai pu démontrer la réexpression du collagène VII in vivo, après injection de différentes doses d’AONs dans des peaux équivalentes générées avec des cellules de patients et greffées sur des souris immunodéficientes. Dans la seconde partie de ma thèse, j’ai étudié une famille EBD particulière, dont les deux enfants atteints présentaient une EBD beaucoup plus sévère que leur mère et leur grand père maternel, atteints d’une forme modérée d’EBDD. Le séquençage des 118 exons de COL7A1 et des régions d’épissage adjacentes a permis d’identifier une seule mutation dominante c.6698G>A (p.Gly2233Asp) dans l’exon 84, à l’état hétérozygote chez les quatre sujets. A partir de l’étude des transcrits paternels, j’ai pu identifier une nouvelle mutation c.2587+40G>A dans l’intron 19 de COL7A1, qui active un site donneur cryptique dans l’intron 19, entraînant sa rétention partielle et la formation d’un codon stop prématuré. La confirmation de la présence de cette seconde mutation, récessive, dans l’ADN des deux enfants a ainsi permis d’expliquer les différences phénotypiques observées, les deux enfants atteints étant hétérozygotes composites pour une mutation dominante et une mutation récessive de COL7A1. Cette mutation récessive constitue la mutation intronique la plus distante des sites consensus d’épissage de COL7A1 et souligne l’importance de l’étude des ARNm pour la recherche de mutations dans le cadre des EBD. Dans une dernière partie de ma thèse, j’ai débuté la caractérisation d’un modèle murin knock-in d’EBDR développé par notre laboratoire, qui mime certaines des caractéristiques phénotypiques des patients EBDR. Mon travail a permis de démontrer in vivo la faisabilité de l’approche par saut d’exons pour COL7A1. Cette première étape importante conduit à développer des études de preuve de principe et de toxicologie dans des modèles animaux, dans la perspective d’une transition vers la clinique. Il illustre également les variations pathologiques d’épissage pouvant faire l’objet d’approches thérapeutiques similaires
Dystrophic Epidermolysis Bullosa (DEB) is a group of rare and severe genetic skin disorders, inherited in a dominant (DDEB) or recessive (RDEB) manner, and characterised by loss of adhesion between the epidermis and the underlying dermis. DEB patients suffer from severe blistering of the skin and mucosae after mild traumas, and in the most severe forms, DEB can be life-threatening. DEB is caused by mutations in the COL7A1 gene encoding type VII collagen that assembles into anchoring fibrils forming key dermo-epidermal adhesion structures. To date, there is no specific treatment for DEB. The first part of my thesis was to develop exon skipping as a therapeutic approach for RDEB. In this work, exon skipping strategy consists in modulating the splicing of a premessenger RNA to induce the skipping of a mutated exon and lead to the synthesis of a shorter but functional protein. Exons 73 and 80 of COL7A1 are of particular interest since they carry many recurrent mutations and their excision preserves the open reading frame. In first instance, we have demonstrated the dispensability of these exons for type VII collagen function in an in vivo xenograft model using RDEB cells transduced with retroviral vectors containing COL7A1 cDNAs, deleted of the sequences of exon 73 or 80. I have subsequently transfected primary RDEB keratinocytes and fibroblasts with antisense oligoribonucleotides (AONs) targeting key splicing regulatory elements of these exons, and achieved efficient skipping of these exons (up to 90%). Western blot and immunocytofluorescence experiments demonstrated significant type VII collagen re-expression (up to 25% of the normal amount) in cells from three RDEB patients. Finally, I have generated skin equivalents with cells of these patients, grafted them on immunodeficient mice and injected different doses of AONs in the grafts, and I have demonstrated type VII collagen re-expression in vivo. In the second part of my thesis, I have studied the case of a particular DEB family, in which two affected children presented a DEB much more severe than their mother and maternal grandfather, suffering from a mild form of DDEB. Sequencing of the 118 exons ofCOL7A1 and of their flanking splice sites, lead to the identification of a single dominant mutation c.6698G>A (p.Gly2233Asp) in exon 84, at the heterozygous state in the four individuals. By carrying out analyses on the paternal transcripts, I have identified a novel c.2587+40G>A recessive mutation in intron 19, which activates a cryptic donor splice site in this intron, leading to its partial retention and to the formation of a premature termination codon. I confirmed the presence of this second, recessive, mutation in the DNA of the two affected children, thus providing an explanation for the observed intrafamilial phenotypic variability: the two affected offsprings being compound heterozygotes for a dominant mutation and a recessive mutation in COL7A1. This novel mutation is the deepest intronic mutation found in COL7A1 so far, and emphasizes the importance of studying COL7A1 at the transcripts level to unravel intronic mutations, understand their molecular consequences and their involvement in the development of the disease. In the last part of my thesis, I have started the characterisation of a knock-in murine model of RDEB generated by our laboratory, which mimics some of the phenotypic characteristics of RDEB patients. My thesis work provided the in vivo demonstration of the feasibility of an exon skipping therapeutic approach for COL7A1. This first important step leads to development of proof of concept studies and toxicological studies in different animal models, with the aim of a clinical translation. It also illustrates the pathological splicing alterations that could benefit from similar approaches

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43

Lieto, Louis D. "Characterization of Epitheliogenesis Imperfecta in Equus caballus". UKnowledge, 2001. http://uknowledge.uky.edu/gradschool_diss/475.

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Epitheliogenesis Imperfecta (EI) is a mechanobullous disease that occurs in newborn American Saddlebred and Belgian Draft foals. Necropsy evaluations of two American Saddlebred foals revealed broad skin lesions, dental abnormalities and oral mucosa lesions. Construction of a partial pedigree showing occurrences of EI in American Saddlebred horses was consistent with a recessive pattern of inheritance. An allelic frequency of 0.04 was estimated for the EI gene. The pathological signs of EI were similar to a disease in humans known as Herlitz Junctional Epidermolysis Bullosa (HJEB). HJEB is caused by a defect in one of the three subunits of the laminin 5 protein (LAM 3, LAM 3 and LAM 2), which leads to a separation of the epidermis from the dermis. Transmission electron microscopy revealed a separation within the lamina lucida at the sites of epidermal/dermal splits in the skin of EI affected foals. This indicated that a defect in the laminin 5 protein was responsible for EI. Linkage disequilibrium (LD) between microsatellite markers and the EI disease locus was tested for in the American Saddlebred and Belgian Draft breeds. Genotyping of microsatellite alleles was used to determine fit to Hardy-Weinberg equilibrium for control and EI populations for both breeds using Chi square analysis. Two microsatellite loci (ASB14 and AHT3) were not in Hardy-Weinberg equilibrium in EI affected American Saddlebred horses. This suggested that the EI disease locus was located on ECA 8, the putative location of LAM 3. No evidence of LD between any of the tested microsatellite loci and the EI locus was observed in the Belgian Draft samples. A cDNA library was built from Thoroughbred horse skin to serve as a resource for sequencing equine skin gene transcripts. 313 ESTs were sequenced, of which 207 were putatively identified (66%) by database search. Examination of the pathology and ultrastructure of EI affected foals and comparison with HJEB indicated that laminin 5 was the responsible defective protein. The LD analysis suggested that LAM 3 was the EI disease locus in American Saddlebred horses.

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44

Solimani, Farzan [Verfasser], e Michael [Akademischer Betreuer] Hertl. "Development and validation of serological immunoassays in laminin γ-1 pemphigoid and epidermolysis bullosa acquisita / Farzan Solimani ; Betreuer: Michael Hertl". Marburg : Philipps-Universität Marburg, 2019. http://d-nb.info/1191368696/34.

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45

Klockemann, Martti [Verfasser], Jennifer [Akademischer Betreuer] Hundt e Marc [Akademischer Betreuer] Ehlers. "Pharmakologische Inhibition des Komplement-5a-Rezeptors bei Antikörpertransfer-induzierter Epidermolysis bullosa acquisita / Martti Klockemann ; Akademische Betreuer: Jennifer Hundt, Marc Ehlers". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2020. http://d-nb.info/1217499172/34.

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46

Uppalapati, Sai Kailash [Verfasser]. "Immune privilege collapse and epithelial stem cell damage during hair follicle inflammation in murine epidermolysis bullosa acquisita (EBA) / Sai Kailash Uppalapati". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2014. http://d-nb.info/1063210437/34.

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47

Fründt, Thorben Wilhelm [Verfasser]. "Entwicklung eines ELISA zum Nachweis zirkulierender Antikörper gegen Kollagen Typ VII im aktiven Mausmodell der Epidermolysis bullosa acquisita / Thorben Wilhelm Fründt". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2011. http://d-nb.info/1010454161/34.

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48

Risteli, M. (Maija). "Substrate specificity of lysyl hydroxylase isoforms and multifunctionality of lysyl hydroxylase 3". Doctoral thesis, University of Oulu, 2008. http://urn.fi/urn:isbn:9789514288296.

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Abstract Lysyl hydroxylase (LH) catalyzes the post-translational formation of hydroxylysines in collagens and collagenous proteins. Three lysyl hydroxylase isoforms, LH1, LH2 and LH3, have been identified from different species. In addition, LH2 has two alternatively spliced forms, LH2a and LH2b. The hydroxylysines have an important role in the formation of the intermolecular collagen crosslinks that stabilize the collagen fibrils. Some of the hydroxylysine residues are further glycosylated. In this thesis the substrate amino acid sequence specificities of the LH isoforms were analyzed using synthetic peptide substrates. The data did not indicate strict amino acid sequence specificity for the LH isoforms. However, there seemed to be a preference for some sequences to be bound and hydroxylated by a certain isoform. Galactosylhydroxylysyl glucosyltransferase (GGT) catalyzes the formation of glucosylgalactosylhydroxylysine. In this study, LH3 was shown to be a multifunctional enzyme, possessing LH and GGT activities. The DXD-like motif, characteristic of many glycosyltransferase families, and the conserved cysteine and leucine residues in the N-terminal part of the LH3 molecule were critical for the GGT activity, but not for the LH activity of the molecule. The GGT/LH3 protein level was found to be decreased in skin fibroblasts and in the culture media of cells collected from members of a Finnish epidermolysis bullosa simplex (EBS) family, which was earlier reported to have a deficiency of GGT activity. In this study, we showed that the reduction of enzyme activity is not due to a mutation or lower expression of the LH3 gene. Our data indicate that the decreased GGT/LH3 activity in cells has an effect on the deposition and organization of the key extracellular matrix components, collagen types VI and I and fibronectin, and these changes are transmitted to the cytoskeletal network. These findings underline LH3 as an important extracellular regulator.

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49

Dures, Emma K. "An exploration of the psychosocial impact of epidermolysis bullosa on the daily lives of affected adults and identification of associated support needs". Thesis, University of the West of England, Bristol, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522538.

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Abstract (sommario):

Epidermolysis Bullosa (EB) is the term used to describe a number of genetically determined disorders characterised by excessive susceptibility of the skin and mucosae to separate from the underlying tissue following mechanical trauma. EB is a rare, life-long and non-curable condition. At its clinically mildest, the blistering occurs on the hands and/or feet and makes holding things and walking extremely painful. In clinically more severe forms, all the body is affected and the wounds heal slowly, giving rise to scarring, an altered physical appearance and significant disability. Despite the potentially severe and restrictive nature of EB, there has been scarcely any published research on its psychosocial impact. However, anecdotal evidence has suggested that those affected can face considerable challenges in their daily lives. This research was undertaken to address the deficit of empirical evidence concerning the ways and extent to which living and working with EB can affect individuals' social, emotional and psychological wellbeing and to identify unmet support needs. Given the exploratory nature of the thesis, a qualitatively-driven mixed method design was employed. A total of four studies were undertaken. The first two studies used an inductive approach. They produced wide-ranging, multi-level data about the many ways in which EB can impact on the daily lives of affected adults and also informed the subsequent quantitative study. The third study used a deductive approach. It examined the role of specific psychosocial variables that had been implicated in the qualitative data in relation to the psychological wellbeing of adults with EB. The fourth study employed mixed methods to explore the impact of working in the field on specialist EB professionals, as understanding their perceptions and experiences is an important aspect of effective care provision. In the final stage of the research, the support needs of adults with EB and EB specialist professionals were identified. Initial recommendations have been made for ways of meeting these needs based on findings from the four studies evaluated in the context of the existing chronic conditions and skin conditions literature.

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Sadeghi, Hengameh [Verfasser]. "The contribution of interleukin-1 and retinoid acid receptor-related orphan receptor alpha to the pathogenesis of epidermolysis bullosa acquisita / Hengameh Sadeghi". Lübeck : Zentrale Hochschulbibliothek Lübeck, 2015. http://d-nb.info/1075027160/34.

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