Dissertations / Theses: 'Associated gene'

1

Hofstra, Robert Martinus Wouter. "The RET gene and its associated diseases." [S.l. : [Groningen] : s.n.] ; [University Library Groningen] [Host], 1995. http://irs.ub.rug.nl/ppn/142201383.

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2

Jones, Richard Julian. "Novel gene therapy for EBV-associated malignancies." Thesis, University of Birmingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274412.

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3

James, Pamela. "Characterization of Novel Lymphoid-Associated Genes Identified by Gene-Trapping: a Dissertation." eScholarship@UMMS, 2006. http://escholarship.umassmed.edu/gsbs_diss/231.

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The discovery of novel genes involved in hematopoietic development and lymphoid function is necessary for the understanding of these systems. To this end, we utilized transmembrane protein-specific gene trapping in embryonic stem (ES) cells, a method of forward genetics, to identify a novel, complex locus from which several splice variants arise. The trapped locus identified in the KST30 ES cell clone encodes several genes including outer membrane protein 25 (OMP25) and activin receptor interacting protein (ARIP2) and two novel genes, AK74 and AK88. AK74 is highly conserved between human and mouse with 85% identity at the amino acid level. The human homolog was cloned from CD34+ cord blood hematopoietic stem cell progenitors (HSCPs) implying that it may have a role in the hematopoietic system. We generated mice from the gene trapped ES cells, called KST30 mice, to analyze the expression pattern of transcripts from the trapped locus in the hematopoietic system. Utilizing the gene trap LacZ reporter and RT-PCR, we found that AK88 and AK74 are expressed in hematopoietic stem cells and thymocytes and that AK88 and ARIP2 are dramatically up-regulated in activated Band T lymphocytes. In addition, we found restricted expression of the gene trap in most non-lymphoid tissues. Interestingly, the expression pattern of the gene trap coincides with the expression of activin signaling components in many cell types including thymocytes, activated B cells, hematopoietic stem cells and the ductal cells of the pancreas. AK74, AK88 and ARIP2 share two exons that encode a 44 amino acid region. ARIP2 negatively regulates activin signaling through endocytosis of Activin type II receptors. The N-terminal PDZ domain associates with ActRII and mediates endocytosis via association with RalBP1. The region of ARIP2 that associates with RalBP1 encompasses the 44 amino acid region also found in AK74 and AK88, suggesting that these proteins may also associate with RalBP1, perhaps sequestering it from ARIP2. This possibility combined with the similarities between gene trap expression and expression of the components of activin signaling indicates a role of the trapped genes in activin signaling. AK74 and AK88 have a signal sequence and transmembrane domain that are predicted to direct them to mitochondria. To confirm this prediction, we examined the subcellular localization of AK74 and found that it localizes to a punctate, perinuclear structure identified as mitochondria using a mitochondria specific dye. AK74 was not seen in the cytoplasm, nucleus or at the plasma membrane of cells. To determine the function of these novel genes, AK74 was retrovirally over-expressed in a double positive thymoma cell line and examined the global expression profile using Affymetrix gene chip. AK74 changed the expression levels of 36 genes greater than 3-fold compared to vector alone. Of these genes, several are involved in cytoskeletal rearrangement, apoptosis or are regulated by calcium signaling. Using yeast two-hybrid, several candidate binding partners for AK74 were identified, one of which is the receptor for activated protein kinase C (RACK1). RACK1 was also identified as a potential binding partner for AK88. RACK1 is a WD40 domain-containing scaffolding protein that has been implicated in many pathways but most prominently in the protein kinase C signaling pathway. Association with RACK1 by either AK74 or AK88 suggests that they may be involved in RACK1 function. Both RACK1 and PKC are involved with Ca2+ signaling through different mechanisms. This, combined with global gene expression changes in AK74 over-expressing cells suggests a role for AK74, AK88 or ARIP2 in Ca2+ signaling. When we examined the expression of the trapped genes in mice homozygous for the gene-trapped allele (KST30tr/tr) we found that insertion of the gene trap caused a severe decrease in AK88 and ARIP2 but not AK74 transcripts. Analysis of KST30tr/tr mice showed no abnormalities in conventional lymphoid populations and precursors, however, intraepithelial lymphocyte (IEL) populations were altered by the loss of AK88 and/or ARIP2. There was an approximate 2-fold decrease CD8αα+ T cells in the small intestine while CD8αβ+ T cells were largely unaltered. Using gene trap technology, we have identified two novel, mitochondria-localized proteins. The cumulative findings described in this thesis, including the homology between AK74, AK88 and ARIP2, their expression pattern and the phenotype of KST30tr/tr mice, suggest possible roles of AK74 and AK88 in diverse pathways.

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Read, Tara. "Elucidating a novel gene associated with myoclonus dystonia." Thesis, University of Ottawa (Canada), 2009. http://hdl.handle.net/10393/28248.

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Myoclonus Dystonia (MD) is an autosomal dominant disease with high but incomplete penetrance and is characterized by both involuntary myoclonic jerks and dystonic posturing. Our group has found that mutations within the epsilon sarcoglycan (SGCE) gene on chromosome 7q21 are associated with MD in 30-40% of affected individuals in 31 families studied, supporting the basis for genetic heterogeneity. Novel mutations have been found in SGCE by screening these families for point mutations and large deletions and duplications through the use of sequencing, high performance liquid chromatography (HPLC) and multi˙ligation probe amplification (MLPA) analysis. A 10cM genome wide linkage analysis of a large Canadian family provided significant LOD scores for microsatellite markers within the 18p11 region, now designated as the DYT 15 locus. Further haplotype analysis has narrowed a non-recombinant region associated with the disease phenotype to a 3.18 Mb region in this locus. Since the current understanding of Myoclonus Dystonia is poor, it is difficult to predict genes that could be responsible for MD. Sarcoglycans are essential constituents of the dystrophin-glycoprotein complex and are involved in linking the extracellular lamanin matrix to the actin filaments within the cytoplasm; therefore focus is given to the examination of potentially related structural genes that are expressed in the brain. By analyzing such candidate genes in a panel of affected individuals, we believe that a novel gene will be elucidated and provide insight into the mechanism of Myoclonus Dystonia.

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Gordon, Linda Anne. "Investigation of potential problems associated with gene therapy." Thesis, University of Leicester, 1998. http://hdl.handle.net/2381/30742.

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Safety requirements for gene therapy currently focus on preventing acute patient toxicity caused by the introduction of exogenous DNA. This project aimed to investigate the possibility that more subtle changes in cell regulation may occur as a result of transfection or transgene expression. Mouse B16.F1 melanoma and CMT93 colorectal cell lines transfected with a plasmid (pNASS) or retroviral (pBabeNeo) construct were used as a model. Expression of the transgene was driven by a 2540bp (plasmid) or 769bp (retroviral) fragment of the mouse tyrosinase promoter. Results have shown that transfection per se can cause small changes in the proliferation rate of B16.F1 and CMT93 cells, but transgene expression did not produce this effect. However, expression of an IL-2 transgene in B16.F1 cells did decrease the rate of substrate attachment via an intracellular mechanics. These data suggest that cell regulation can be disrupted by transfection and transgene expression. Despite these changes, DDRT-PCR analysis of approximately 25% of the mRNA population indicated few changes in gene expression between parental and transfected cells. Loss of transgene expression has proved an obstacle to success in clinical trials and was observed in both cell lines. In B16.F1 cells containing pNASS/IL-2, levels of IL-2 protein were reduced by more than 90% after 15 weeks in culture and this was mirrored by a decrease in IL-2 mRNA levels. The transgene was intact in high passage cells and restriction digest analysis did not indicate changes in methylation status. The continued presence of the construct was confirmed by treatment with 10-6 M melanocyte stimulating hormone, which induced IL-2 trnasgene mRNA and protein expression in cells that had lost expression from pNASS/IL-2. Induction was not observed in cells with the shorter promoter fragment in pBabeNeo/IL-2, indicating that the mechanism of downregulation can be overridden if the promoter contains suitable response elements.

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Behrens, Renee F. "Changes in endometrial gene expression associated with Infertility." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511836.

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Sawhney, Namita. "Studies of the growth arrest associated gene - prohibitin." Thesis, King's College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261713.

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Glod, Frank. "PCR generated gene probes for cloning fungal polykeptide synthase genes associated with squalestatin biosynthesis." Thesis, University of Bristol, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268525.

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9

John, Christopher Robert. "Gene expression associated with the evolution of C₄ photosynthesis." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709401.

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10

Childs, Andrew James. "Tex19 : a germ cell-specific gene associated with pluripotency." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/29064.

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Germ cells are the only population of cells in the adult organism shown to retain pluripotency – the ability to differentiate into all the different germ layers of the embryo. This property is shared with embryonic stem cells and tumour-derived embryonal carcinoma cells, and the molecular mechanisms underpinning pluripotency are likely to be similar in all three systems. The core circuitry of transcription factors required to establish and maintain pluripotency is relatively well characterised. However, many of these important transcription factors also regulate a large number of genes involved in processes other than transcription, some of which may also play an important role in maintaining stem cell plasticity. Understanding the entire molecular basis of pluripotency will improve the use of ES cells as a model system for differentiation and development, enhance the therapeutic potential of stem cells and provide insights into the mechanisms of tumourigenesis. Testis Expressed Gene 19 has been identified in screens for genes expressed in spermatogonia, embryonic stem cells, and for targets of translational regulation by the germ cell-specific protein Dazl. The work presented here characterises the expression pattern of Tex19 in the gonads and stem cells, establishing a correlation between the expression of Tex19 and pluripotent potentiality. A human homologue of Tex19 is found to be expressed in stem cells and cancer, and the evolution of the gene family in mammals is investigated. Finally, the function of Tex19 and its relationship with Dazl is also investigated.

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11

Bandekar, Aditya C. "Cell Cycle Associated Gene Expression Predicts Function in Mycobacteria." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1068.

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While the major events in prokaryotic cell cycle progression are likely to be coordinated with transcriptional and metabolic changes, these processes remain poorly characterized. Unlike many rapidly-growing bacteria, DNA replication and cell division are temporally-resolved in mycobacteria, making these slow-growing organisms a potentially useful system to investigate the prokaryotic cell cycle. To determine if cell-cycle dependent gene regulation occurs in mycobacteria, we characterized the temporal changes in the transcriptome of synchronously replicating populations of Mycobacterium tuberculosis (Mtb). By enriching for genes that display a sinusoidal expression pattern, we discover 485 genes that oscillate with a period consistent with the cell cycle. During cytokinesis, the timing of gene induction could be used to predict the timing of gene function, as mRNA abundance was found to correlate with the order in which proteins were recruited to the developing septum. Similarly, the expression pattern of primary metabolic genes could be used to predict the relative importance of these pathways for different cell cycle processes. Pyrimidine synthetic genes peaked during DNA replication and their depletion caused a filamentation phenotype that phenocopied defects in this process. In contrast, the IMP dehydrogenase guaB2 dedicated to guanosine synthesis displayed the opposite expression pattern and its depletion perturbed septation. Together, these data imply obligate coordination between primary metabolism and cell division, and identify periodically regulated genes that can be related to specific cell biological functions.

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12

Miller, Jennifer Dawn. "Senescence-associated gene expression in ozone-stressed Arabidopsis leaves." Adobe Acrobat reader required to view the full dissertation. Adobe Acrobat reader required to view the full dissertation, 2000. http://etda.libraries.psu.edu/theses/available/etd-0626100-201030/.

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Thesis (Ph. D.)--Pennsylvania State University, 2000.
Accompanied by: Senescence-associated gene expression during ozone-induced leaf senescence in Arabidopsis. 1015-1023 p. : ill. (some col.) ; 28 cm. Published in Plant physiology, August, 1999, v. 120. Availabe online.

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13

Cesar, Aline Silva Mello. "Identification of genes associated with intramuscular fat deposition and composition in Nellore breed." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/11/11139/tde-12082014-103102/.

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The amount and composition of intramuscular fat (IMF) influence the sensory characteristics, nutritional value of beef and human health. The amount of fatty acid and its composition in beef varies by breed, nutrition, sex, age or carcass finishing level. The fat deposition and composition are determined by many genes that participate directly or indirectly in adipogenesis and lipid metabolism. The selection of animals with fat amount and composition suitable for the consumer is complex due to high cost of measurement, the moderate heritability and polygenic traits (many genes are involved with these traits). In the last decade with a great advance in bovine genomics resulted in the complete genome sequencing and the development of high-density chips of SNPs. This scientific advance jointly with technological improvement allowed the identification of genes responsible for important quantitative traits in cattle. This study aimed to identify and characterize genes associated with the deposition and composition of intramuscular fat in Nellore. A genome-wide association study (genome- wide association studies, GWAS) was performed to identify genomic regions associated with traits of interest and positional candidate genes. A total RNA sequencing (RNA-Seq) analysis was applied to transcriptome study of Longissimus dorsi muscle. Three hundred and eighty six Nellore steers were used for the evaluation of lipid content and fatty acid profile of LD, and genotyping with high-density chip SNP (SNP800 Illumina BeadChip). A subset of 14 animals, seven animals for each extremes of genomic estimated values (GEBV) were used to RNA-Seq analysis. Twenty-five genomic regions (1 MB window) were associated with the deposition and composition of intramuscular fat, which explained >= 1 % of the genetic variance. These regions were identified on chromosomes 2, 3, 6, 7, 8, 9, 10, 11, 12, 17, 26 and 27, many of these have not previously been found in other breeds and in these regions important genes were identified. Genomic regions and genes identified and presented here should be contribute to a better understanding of the genetic control of deposition and fat composition in beef cattle, and can be applied in breeding programs for animals that produce a quality and healthy beef to human consumers.
A quantidade e composição da gordura intramuscular (GIM) pode influenciar as características sensoriais, o valor nutricional da carne bovina e na saúde humana. O perfil dos seus ácidos graxos pode se apresentar de maneira diversificada conforme a genética, o manejo e a nutrição dos animais de origem. A deposição e composição da gordura são determinadas por muitos genes que participam direta ou indiretamente da adipogênese e do metabolismo lipídico. A seleção de animais com teor e composição de gordura adequado para o consumidor é complexa pela difícil mensuração destas características, pela moderada herdabilidade e pelo desconhecimento dos genes envolvidos. Na última década, presenciamos um grande avanço na área da genômica bovina que resultou no sequenciamento completo do genoma e no desenvolvimento de chips de alta densidade de SNP. Este progresso científico, aliado aos avanços tecnológicos de equipamentos, resultou na identificação de genes responsáveis pela determinação de características quantitativas de interesse científico e comercial na bovinocultura. Este estudo teve como objetivo identificar e caracterizar genes associados à deposição e composição de gordura intramuscular em bovinos Nelore. Para este fim foi conduzido um estudo de associação genômica (Genome-wide association studies, GWAS) para identificar regiões genômicas associadas às características de interesse e identificar genes candidatos posicionais. Para o estudo de expressão diferencial foi conduzido um estudo do transcriptoma a partir do sequenciamento de RNA total (RNA-Seq) do músculo Longissimus dorsi. Foram utilizados 386 Nelores para a avaliação do teor de lipídeos total e perfil de ácidos graxos do músculo LD e, genotipagem com chip de alta densidade de SNP (Illumina SNP800 BeadChip). Um subconjunto de 14 animais, sendo sete animais de cada extremo para os valores genômicos estimados (GEBV) foi utilizado para o estudo de RNA-Seq. Foram encontradas 25 regiões genômicas (intervalos de 1 MB) associadas com deposição e composição de gordura intramuscular, as quais explicaram >= 1% da variância genética. Estas regiões foram identificadas nos cromossomos 2, 3, 6, 7, 8, 9, 10, 11, 12, 17, 26 e 27, muitas destas não foram previamente detectadas em outras raças. Nestas regiões foram identificados importantes genes e podem ajudar no entendimento da base genética envolvida na deposição e composição de gordura. As regiões genômicas e genes aqui identificados e apresentados contribuem para um melhor entendimento do controle genético da deposição e composição de gordura em gado de corte e ainda podem ser aplicados em programas de seleção genética de animais que produzam carne com qualidade e com perfil de gordura saudável ao homem.

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14

Smajlovic, Dzenan. "Bestämning av FTO (Fat mass and obesity associated gene) polymorfism." Thesis, University of Kalmar, School of Pure and Applied Natural Sciences, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:hik:diva-804.

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Vetenskapen har på senare år försökt fastställa de olika orsaker som leder till fetma. Det är känt att högt energiintag och för lite motion för eller senare hos de flesta individer resulterar i fetma. Det som kan konstateras är att ärftlighet i samspel med miljön vi lever i och påverkas av kan vara den huvudsakliga orsaken till en rad sjukdomar inklusive fetma. På senare år har forskare upptäckt olika gener som på ett eller annan sett är involverade i ämnesomsättningen. En sådan gen är ”fat mass and obesity associated gene”, FTO. Denna gen återfinns på kromosom 16 och har en storlek på 410 kilobaspar. Genen består av nio kodande områden, exoner, och 8 icke kodande områden, introner. Genens funktion är inte fastställd men den tycks både reglera ämnesomsättningen och lipolysen i kroppen. Tidigare studier har konstaterat att en specifik polymorfi i nukleotid rs9939609 medför ökad risk för sjuklig fetma. Uppsättningen som förekommer i nukleotiden uttrycks med A och T. Där dubbel uppsättning av A- allelen klassas som ärftlig risk för fetma. Syftet med detta examensprojekt är att bestämma polymorfi hos FTO genen med hjälp av två olika pyrosekvenserings- baserade metoder. Metod 1 bygger på extraktion av DNA från helblod, sedan amplifiering med PCR och slutligen pyrosekvensering. Metod 2, som jämfördes med metod 1, bygger på PCR direkt på helblod och pyrosekvensering. Blod från 97 friska individer analyserades. Med metod 1 konstaterades förekomst av följande genotyper i provmaterialet, 11 A/A homozygota, det vill säga har riskallelen för fetma i dubbeluppsättning, 50 A/T heterozygota och 36 T/T, vildtyp, som står för minskad ärftlig risk för fetma respektive ingen alls. Med metod 2 som skulle testas, visade sig resultatet överensstämma med metod 1. Med metod 2 erhölls följande resultat 11 A/A, 49 A/T och 34 T/T. Med metod 2 kunde inte 3 prov analyseras. Slutsatsen som kan dras utifrån studien i detta projekt är att metod 2 är likvärdig metod 1 ur analyssynpunkt. Metod 2 är arbetsbesparande tidsmässigt och även billigare då DNA extraktionssteget inte behöver genomföras.

2008:BL10

Science has for a long time looked for an answer for obesity. Obesity is often explained as the problem of the energy we eat and don’t use, but obesity might also have hereditary causes, where specific genes might play an important role. One of the recent genes found is the fat mass and obesity associated gene, FTO, which is located on chormosome 16 and has a size of 410 kilobasepairs. The gene is composed of nine exons and eight introns. The function of the gene is not known in detail, but studies has indicated that the gene could play a part in regulating the metabolism and fat cell lipolysis. The purpose with this examination degree project was to compare two methods for analysis of polymorphism in the FTO gene. Method 1 is based on DNA purification from whole blood, amplification with PCR, and finally detection using pyrosequencing. In method 2 PCR is performed on whole blood directly without prior DNA purification. Pyrosequencing was used with this method also to detect the polymorphism. Earlier studies have shown that theSNP (single nucleotid polymorphism) rs9939609, is associated with increased risk for obesity. Results obtained using method 1 were, 11 individuals had the A/A genotype, 50 was heterozygous (A/T), and 36 the wild type form (T/T), that is not associated with an increased risk for obesity. With method 2, the same result as with method 1 was obtained for the 94 samples of blood analyzed; 11 A/A, 49 A/T and 34 T/T were obtained. Remaining three samples of the 97 analyzed, failed in the pyrosequencing with method 2.

The conclusions with this degreeprojcet were that method 1 and 2 gave the same results. Method 2 is recommended as it is faster and less expensive, as no prior DNA purification is needed.

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Lam, T. H. Jason. "Differential gene expression associated with phenotypic virulence of mycobacterium tuberculosis." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B37769005.

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Lam, T. H. Jason, and 林梓軒. "Differential gene expression associated with phenotypic virulence of mycobacterium tuberculosis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B37769005.

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17

Escaler, Margarita. "Changes in host gene expression associated with plant virus replication." Thesis, University of East Anglia, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302215.

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18

Marbiah, M. "Identification of a gene regulatory network associated with prion replication." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1469415/.

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Prion diseases are fatal, transmissible neurodegenerative diseases which are associated with the conversion of host encoded prion protein, PrPC, into an aggregated, proteinase-resistant isoform, termed PrPSc. Coding polymorphisms within Prnp, the gene encoding PrPC, are known to affect disease incubation times and susceptibility in human, mouse, and sheep and the most prominent example, codon 129 polymorphism in humans, has major disease modifying effects. However, significant differences in incubation times for scrapie in mice with the same Prnp genotype indicate a major role of PrP-independent genetic factors. To identify these factors, prion-resistant revertants were isolated from a highly prion-susceptible cell clone and the respective transcriptomes were analysed. Remarkably, incubation of revertants with the differentiation agent retinoic acid led to a forty-fold increase in prion propagation rates and downregulation of previously identified differentially expressed genes. This approach led to identification of a gene signature of eighteen genes associated with susceptibility to prion propagation and regulated by differentiation. The experimental validation of the relationship between gene expression and prion propagation by transcriptional silencing confirmed the role of nine genes, expressed in revertants. Several susceptibility genes encode proteins that are involved in the regulation of the extracellular matrix (ECM), a site where disease associated PrP (PrPd) is found. Further experimentation revealed novel insights on how expression of these encoded proteins modulate prion replication mechanistically. Inhibition of fibronectin1 binding to integrin α8 by the RGD peptide significantly decreased the activation of matrix metalloproteinase (MMP)-2/9 whilst prion propagation rates increased. Moreover, Papss2 loss-of-function led to undersulphation of heparan sulphate with a concomitant increase in prion propagation. Remarkably, under these conditions, PrPC was deposited at the ECM. The observation that Neural cell adhesion molecule (Ncam) colocalised with PrPd at the basement membrane of infected, but not of uninfected cells led us to scrutinise membrane microdomains in uninfected and chronically infected cells. Co labelling experiments provided evidence for colocalisation of PrPd with tetraspanin-containing microdomains and GM1 domains. The significance of this finding has yet to be determined. In summary, we have identified a gene regulatory network associated with prion propagation at the ECM which is governed by the cellular differentiation state. Work is currently in progress to determine the functional relevance of the identified genes in vivo.

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Aravani, Dimitra. "Functional analysis of the coronary artery disease associated gene HHIPL1." Thesis, University of Leicester, 2017. http://hdl.handle.net/2381/39349.

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Genome-wide association studies have identified chromosome 14q32 as a locus for coronary artery disease in humans. The disease associated variants fall in a gene called Hedgehog interacting protein-like 1 (HHIPL1), which encodes an uncharacterised sequence homologue of an antagonist of Hedgehog signalling. Here, is presented the investigation of HHIPL1 function and its role in atherosclerosis. In vitro analysis was undertaken in order to determine the molecular and cellular function of the protein. Epitope tagged HHIPL1 protein was present in the media of transfected cells and immunoprecipitated with GFP tagged Sonic Hedgehog (SHH) protein, demonstrating that HHIPL1 is a secreted interactor of SHH. HHIPL1 gene expression was also measured in cardiovascular cell types and found that it is expressed in aortic smooth muscle cells (HASMC), but not in other disease relevant cell types. During atherogenesis smooth muscle cells migrate and proliferate into the tunica intima. Therefore, the effect of HHIPL1 on HASMC phenotype was examined following HHIPL1 knockdown. Down regulation of HHIPL1 through siRNA resulted in a significant reduction in both HASMC proliferation and migration, suggesting a regulatory role for HHIPL1 in smooth muscle cell phenotype. Next, the role of HHIPL1 in atherosclerosis in vivo was examined. In atherosclerotic mouse aortas (Apoe-/-) Hhipl1 expression increased with disease progression. In order to further investigate the effect of Hhipl1 on atherosclerosis Hhipl1 knockout mice, which are phenotypically normal, were crossed onto two hyperlipidemic atherosclerosis prone backgrounds. Double knockout mice (Hhipl1-/-; Apoe-/-, Hhipl1-/-; Ldlr-/-) displayed a sunstantial reduction of over 60% in atherosclerotic lesion size compared with controls. Moreover, Hhipl1-/- lesions were characterised by reduced smooth muscle cell content, but unaltered lipid and macrophage profile. These data represent the first experimental investigation of HHIPL1 and demonstrate that HHIPL1 is a proatherogenic protein that regulates smooth muscle cell proliferation and migration, presumably through its involvement in Hedgehog signalling.

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Ndima, Tozama Beauty. "Gene expression associated with drought tolerance in Xerophyta viscosa Baker." Master's thesis, University of Cape Town, 2000. http://hdl.handle.net/11427/4309.

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Bibliography: leaves 89-100.
Herophyta viscosa (Baker) is a monocytyledonous resurrection plant that can tolerate extremes of dessication. Upon rewatering, it rehydrates completely and assumes its full physiological activities. Studies on changes in gene expression associated with dehydration stress tolerance were conducted. A cDNA library constructed from m RNA isolated from dehydrated (85%, 37% and 5% relative water content) X. viscosa leaves, was differently screened. Of the 192 randomly selected cDNAs screened, 30 showed higher expression levels when X. viscosa was dehydrated while 20 showed lower expession. XVLEA, XVDH and XVLEC represent three cDNAs that were upregulated during dehydration stress. XVLEA showed the highest identity at the amino acid level with a late embryogenesis abundant protein, LEA29G, from Gossipium hirsutum (30%) and LEA D-29 from cotton (50%). XVDH exhibited significant identity to dehydrin proteins from Arabidopsis thaliana (45%) and Pisum sativum (43%) at the amino acid level. It encodes a glycine-rich protein (27kDa) which is largely hydrophilic and contains a hydrophobic segment at the C-terminus. XVLEC showed 28% identity and 50% similarity to a lectin-like protein from Arabidopsis thaliana. Southern blot analysis confirmed the presence of the three cDNAs in the X.viscosa genome. Both XVLEA and XVDH transcripts were highly expressed during dehydration- (37% RWC) and rehydration (4%, 32%, 72% RWC) treatment of the plant ͌ 1.0kb was observed. However, with XVDH a transcript of ͌ 1.0 kb and 1.09 kb were observed. XVDH transcripts accumulated in X. viscosa plants in response to low temperature, heat and dehydration stresses, as well as to exogenous supply of abscisic acid, ethylene and methyl jasmonate. Localization studies of the XVDH encoded protein showed that XVDH is located in the plasma membrane-cell wall region.

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21

Asghar, Mobin. "Epstein-Barr virus associated diseases : immunotherapy and cytokine gene expression." Thesis, University of Edinburgh, 2001. http://hdl.handle.net/1842/22388.

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The aim of the first study was to use the SCID model to investigate the effect of varying doses of human unmanipulated peripheral blood mononuclear cells (PBMC), polyclonal and EBV peptide-specific cytotoxic T cell lines (CTL) on outgrowth and therapy of autologous LCL tumours. Effector cells were mixed with fixed tumorigenic dose of autologous LCL cells at varying ratios and injected s/c into SCID mice. Unmanipulated PBMC failed to control the outgrowth of LCL tumours. Polyclonal CTLs prevented tumour outgrowth down to the CTL:LCL ratio of 0.25:1 suggesting that outgrowth of EBV-positive tumours is effectively controlled by autologous EBV-specific CTLs. Polyclonal CTLs also improved survival of SCID mice with already established autologous LCL tumours. Positive effect of CTL on survival and tumour mass reduction was greater in animals with small tumour mass at start of therapy as compared to those with larger tumours. Delivery of multiple CTL infusions via the intravenous (I/V) route was more effective in reducing tumour mass than injection of a single fixed doses via the I/V or intratumour route. In contrast, only the EBV peptide-specific CTLs with a higher frequency of detectable precursors in the peripheral blood prevented tumour outgrowth below CTL:LCL ratio of 1:1. Peptide-specific CTLs targeting an immunodominant LMP1 epitope also successfully controlled outgrowth of LCL tumours below CTL:LCL ratio of 1:1, suggesting the possible extension of CTL therapy to EBV positive malignancies with restricted EBV gene expression patterns. The second study investigated the cytokine gene expression pattern of EBV associated diseases. Dysregulation of the cytokine network has been proposed as a cofactor in pathogenesis of EBV related conditions. Higher level of cytokine gene expression has been found in lymphoid tissue of patients with IM as compared to normal individuals and in cases of EBV positive PTLD, HD and NPC as compared to EBV negative cases.

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22

Wang, Qingliang. "QRX, a novel homeobox gene, is associated with retinal degeneration." Available to US Hopkins community, 2002. http://wwwlib.umi.com/dissertations/dlnow/3068223.

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23

Raskopp, Stina. "UNDERSTANDING MICROBE REGULATION OF THE PARKINSON DISEASE ASSOCIATED GENE LRRK2." Thesis, KTH, Skolan för kemi, bioteknologi och hälsa (CBH), 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-237742.

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Microbiota’s influence on human health and disease is a growing research field including neurodegenerative diseases such as Parkinson’s disease (PD). The disease symptoms involve movement disorder, manifesting tremor, rigidity, bradykinesia and instability. At the molecular level, the disease exhibits; aggregated alfa-synuclein trapped inside neurons in the brain, in so called Lewy bodies, and loss of dopaminergic neurons in substantia nigra.The working hypothesis of this project is that human microbiome composition and interactions mediate environment and lifestyle influences on disease expression of PD. To validate this hypothesis, a mouse model (C57BL/J6 mice) was used. Two knock-in mouse lines were used; one carrying the wild type, human Leucine-Rich-Repeat-Kinase 2 (LRRK2) and the second carrying the most common Caucasian LRKK2/G2019S mutant. LRRK2 is a tyrosine kinase known to interact with Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a cytosolic microbe peptide sensing receptor. To establish the tools and knowledge required for the analyses, the initial part of the project was to analyze the expression levels of LRRK2 and NOD2 in wild-type C57BL/J6 mice in specific pathogen free (SPF), and mice devoid of exposure to living microbes, so called germ-free (GF) mice. Along with this analyse, expression levels of the transgenic LRKK2 proteins in the genetically modified mice was monitored. The focus was on the following tissues: striatum, midbrain, hippocampus, small intestine and large intestine and applied immune-histochemistry (IHC) combined with Western blot analysis.Results; significantly higher expression levels of LRRK2 were observed in microbe exposed mice versus GF mice with the exception of the large intestine which showed the opposite. Moreover, NOD2 showed a trend of lower expression levels in all brain GF areas tested with the exception to striatum. For the transgenic human knock-in LRKK2 proteins, increased expression of hLRKK2 were observed in striatum and large intestine compared to G2019S. Reduced hLRKK2 expression was observed in midbrain. The results suggest a strong correlation between LRRK2 expression and the gut microbiota and a need for continued research to better understand the role our indigenous microbiome may play in onset/progression of PD.
Mikroflorans betydelse för människors hälsa och sjukdomar är ett framväxande och banbrytande forskningsfält. Forskning har inte bara visat på mikroflorans betydelse för friska tillstånd utan också för utveckling av sjukdomar, så som Parkinsons sjukdom (PD). PD är en neurodegenerativ sjukdom med symptom som innefattar rörelsestörningar; tremor, stelhet, bradykinesi och instabilitet. På molekylär nivå ses aggregerat alfa-synuclein inuti neuroner i hjärnan, i så kallade Lewy-kroppar samt förlust av dopaminerga neuroner i substantia nigra.Hypotesen som utformats i detta projekt utgick ifrån att mikroflorans sammansättning och interaktioner, medierar miljö- och livsstilsfaktorer vilket leder till utveckling av PD. För att testa hypotesen användes musmodellen C57BL / J6 i vildtyp form samt i transgen form. De transgena formerna bestod av två olika knock-in modeller; en som bär den vilda typen av humant Leucin-Rich-Repeat-Kinase 2 (hLRRK2) och en som bär den vanligaste kaukasiska mutationen av samma protein, G2019S. LRRK2 är ett tyrosin kinas som interagerar med Nucleotide-binding-oligomerization-domain-containing-protein 2 (NOD2), en cytosolisk mikrobpeptidreceptor. Analyser av LRRK2 och NOD2 utfördes på vildtypen av C57BL / J6-möss i specifikt patogenfria (SPF) förhållanden samt på möss som saknar exponering för levande mikrober, så kallade bakteriefria (GF). I de transgena mössen analyserades de genetiskt modifierade LRKK2-proteinerna, hLRRK2 och G2019S, samt NOD2 i möss i SPF förhållanden. Följande vävnader undersöktes; striatum, mellanhjärnan, hippocampus, tunntarmen och tjocktarmen med immunhistokemi (IHC) i kombination med Western blot-analys.Resultaten visade på en betydligt högre uttrycksnivå av LRRK2 i mikrobexponerade möss jämfört med GF möss med undantag för tjocktarmen där resultatet visade det motsatta. Dessutom visade resultaten en trend på lägre uttrycksnivåer av NOD2 i alla analyserade områden i hjärnan med undantag för striatum. För de transgena humana knock-in-LRKK2-proteinerna observerades ökat uttryck av LRKK2 i striatum och tjocktarm jämfört med G2019S, samt reducerat LRKK2 uttryck i mellanhjärnan. Resultaten visar på en stark korrelation mellan LRRK2-uttryck och tarmens mikroflora och implicerar förbättrad förståelse av mikroflorans roll i början och under progression av PD.

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Herr, Taylor(Taylor J. ). "Dissecting the gene-regulatory circuitry of disease-associated genetic variants." Thesis, Massachusetts Institute of Technology, 2017. https://hdl.handle.net/1721.1/124573.

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This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Thesis: M. Eng., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2019
Cataloged from student-submitted PDF version of thesis. "June 2019."
Includes bibliographical references (pages 89-91).
Disease-associated nucleotides lie primarily in non-coding regions, increasing the urgency of understanding how gene-regulatory circuitry impacts human disease. Here, we use the increasing availability of functional genomics datasets and models elucidating how regulatory proteins control genes, to evaluate the impact of genetic variants on the activity of diverse regulators. First, we generate a comprehensive compendium of predicted binding intensities across the entire genome for over 500 transcription factors. Second, we create a novel dataset to connect how these binding intensities change in the context of disease datasets. Third, we develop a statistical framework to integrate these two datasets using dimensionality reduction, latent cluster discovery, and topic modeling. We use these techniques to show that regulatory proteins with analogous biological functions share similar global changes in binding due to genome-wide genetic variation. We also use our framework to discover a latent set of topics behind all genomic locations in chromosome 1, to link the locations in each of the topic clusters with a class of related diseases, and to show that relevant biological processes are statistically enriched in the genomic locations most related to each cluster.
by Taylor Herr.
M. Eng.
M.Eng. Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science

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Ye, Chaoyang. "Transcription regulation of adeno-associated viruses." Diss., Columbia, Mo. : University of Missouri-Columbia, 2007. http://hdl.handle.net/10355/4709.

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Thesis (Ph. D.)--University of Missouri-Columbia, 2007.
"May 2007" The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. Includes bibliographical references.

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Bendahmane, Abdelhafid. "Analysis of a gene-for-gene interaction associated with Rx-mediated resistance to potato virus X." Thesis, University of East Anglia, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389350.

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Seago, Julian. "Characterisation of ribonucleases and associated factors in Drosophila melanogaster." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343361.

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Sen, Rwik. "REGULATION OF EUKARYOTIC TRANSCRIPTIONAL ELONGATION AND ASSOCIATED DNA REPAIR." OpenSIUC, 2016. https://opensiuc.lib.siu.edu/dissertations/1205.

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Transcriptional elongation is a crucial step in eukaryotic gene regulation whose mis-regulation leads to cellular pathologies. This makes it quite imperative to aim for a better understanding of the processes regulating transcriptional elongation. An important process promoting the association of RNA Polymerase II (RNAPII) with the coding region of the active gene and hence transcriptional elongation is the monoubiquitination of histone H2B at lysine 123. A complex of an E2 conjugase, Rad6p, and an E3 ligase, Bre1p, is essential for this process. Consistent with the role of histone H2B monoubiquitination in promoting the association of RNAPII with the active gene, this process was found to be impaired in the absence of Rad6p or point mutation of lysine 123 to arginine (H2B-K123R). Intriguingly, the association of RNAPII with the coding region of the active gene was not impaired in the absence of Bre1p, even though Bre1p is essential for histone H2B monoubiquitination. However, deletion of Bre1p’s RING domain that is essential for histone H2B monoubiquitination led to an impaired RNAPII association with the active gene. This observation indicates a role of the non-RING domain of Bre1p in repressing the association of RNAPII with the active gene, resulting in no net decrease in RNAPII occupancy in the absence of Bre1p. Taken together, my results implicated both the stimulatory and repressive roles of the histone H2B ubiquitin ligase Bre1p in regulation of RNAPII association with the coding regions of active genes and hence transcriptional elongation. Interestingly, my work also revealed that for efficient transcriptional elongation by histone H2B monoubiquitination, its optimum level needs to be maintained by a proper balance between Rad6p-Bre1p-mediated ubiquitination and de-ubiquitination (DUB) by the DUB module of SAGA. It was found that Sus1p, a subunit of the DUB module, promotes transcriptional elongation, DNA repair and replication via regulation of histone H2B DUB. In addition to Rad6p- Bre1p and the DUB module, global level of histone H2B monoubiquitination is also critically regulated by Cdk9, a kinase essential for phosphorylation of the serine 2 residue in the C-terminal domain (CTD) of RNAPII, which promotes transcriptional elongation. Apart from serine phosphorylation, proline residues at RNAPII-CTD undergo isomerization by proline isomerases, which also regulate transcription. One of the proline isomerases, Rrd1p, has been previously implicated in transcription in response to rapamycin treatment. Based on this fact and Rrd1p’s known interaction with RNAPII-CTD, we predicted that Rrd1p might regulate transcription independently of rapamycin treatment. In agreement with this hypothesis, our work revealed Rrd1p’s role in facilitating transcription of both rapamycin responsive and non-responsive genes in the absence of rapamycin treatment. Consistently, the absence of Rrd1p led to an impaired nucleosomal disassembly at the active gene, which correlates with the role of Rrd1p in promoting transcription. This is because maintenance of proper nucleosomal dynamics is essential for efficient transcription. It is known that transcriptional elongation is facilitated by the regulation of nucleosomal dynamics via the histone chaperone, FACT. Efficient chromatin reassembly in the wake of elongating RNAPII contributing to the fidelity of transcription is promoted by FACT. Being evolutionarily conserved among eukaryotes, FACT is also known to regulate DNA replication and repair, apart from transcription. Intriguingly, FACT has been found to be upregulated in cancers while its downregulation leads to tumor cell death. However, the mechanism which fine-tunes FACT for normal cellular functions remained unknown. My studies revealed a novel mechanism of regulation of FACT by the ubiquitin-proteasome system in yeast. San1p, an E3 ligase involved in nuclear protein quality control, was found to associate with the active gene and regulate transcriptional elongation through its E3 ligase activity- mediated turnover of Spt16p component of FACT. This regulation was found to maintain optimum level of Spt16p/FACT to engage with the active gene for proper transcriptional elongation, DNA repair and replication. In spite of playing such crucial roles in gene regulation, it was not known how FACT is targeted to the active gene. We discovered that a direct physical interaction between FACT and Cet1p, the mRNA capping enzyme, targets FACT to the active gene independently of Cet1p’s mRNA capping activity. Such targeting of FACT to the active gene leads to the release of promoter proximally paused-RNAPII into transcriptional elongation. However, the progress of RNAPII along the active gene during transcriptional elongation is frequently impeded by various kinds of damages along the underlying template DNA. Even though some of these lesions are co-transcriptionally repaired, it was not known whether the repair of extremely toxic DNA double-strand breaks (DSBs) was coupled to transcription. My results showed that DSBs at the transcriptionally active state of a gene are repaired faster than at the inactive state but such repair was not mediated by a co-transcriptional recruitment of DSB repair factors. This observation is in contrast to other DNA repair pathways such as nucleotide excision repair (NER) where repair factors are co-transcriptionally recruited to the lesion containing DNA. In this regard, we found that an NER factor, Rad14p, co-transcriptionally associates with the active gene in the absence of DNA damage to promote transcription, which unraveled a new role of Rad14p in transcription in addition its established role in NER. In summary, my results provide significant novel insights into the regulation of transcriptional elongation and associated processes leading to better understanding of eukaryotic gene expression.

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Ameen, Gazala. "Cloning and Characterization of rcs5, Spot Blotch Resistance Gene and Pathogen Induced Nec3 Gene Involved in Programmed Cell Death in Barley." Diss., North Dakota State University, 2019. https://hdl.handle.net/10365/29962.

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Upon sensing pathogens, plants initiating defense responses typically resulting in programmed cell death (PCD). PCD effectively subdues biotrophic pathogens but is hijacked by necrotrophs that colonize the resulting dead tissues. We showed that barley wall associated kinase (WAK) genes, underlying the rcs5 QTL, are manipulated by the necrotrophic fungal pathogen Bipolaris sorokiniana to cause spot blotch disease. The rcs5 genetic interval was delimited to ~0.23 cM, representing an ~234 kb genomic region containing four WAK genes, designated HvWak2, Sbs1, Sbs2, and HvWak5. Post-transcriptional gene silencing of Sbs1&2 in the susceptible barley cultivars Steptoe and Harrington resulted in resistance, suggesting a dominant susceptibility function. Sbs1&2 expression is undetectable in barley prior to pathogen challenge; however, specific upregulation of Sbs1&2 occurred in the susceptible lines post inoculation. Promotor sequence polymorphisms were identified in the allele analysis of Sbs1&2 from eight resistant and two susceptible barley lines, which supported the possible role of promotor regulation by virulent isolates contributing to susceptibility. Apoplastic wash fluids from virulent isolates induced Sbs1expression, suggesting regulation by an apoplastic-secreted effector. Thus, the Sbs1&2 genes are the first susceptibility/resistance genes that confer resistance against spot blotch, a disease that threatens barley and wheat production worldwide. The nec3 mutants of barley are hyper-susceptible to many necrotrophs and show distinctive cream to orange necrotic lesions that are induced by infection, representing aberrant PCD. The ?- irradiation induced necrotic mutant, nec3-?1 (Bowman) was confirmed as a nec3 mutant by allelism tests. The F2 progeny of a cross of nec3 x Quest inoculated with B. sorokiniana segregated as a single recessive gene fitting a 3 WT: 1 mutant ratio. The homozygous F2 mutant progeny were genotyped with four SSR and 25 SNP markers at nec3 locus on chromosome 6H, a physical region spanning ~ 16.96 Mb containing 91 high and low confidence annotated genes. Exome capture sequencing of nec3 mutants failed to identify a candidate gene, however, RNAseq analysis identified two candidates in the nec3 region with >three-fold downregulation. We hypothesize that the underlying aberrant PCD mechanism in the nec3 barley mutant facilitates extreme susceptibility to multiple adapted fungal pathogens of barley.

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Dauletbekov, Daniyar. "Adeno-associated virus mediated rhodopsin delivery in preventing secondary cone degeneration in rhodopsin knockout mice." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:041ef367-7ce6-467e-8988-b9735231bdf2.

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Rhodopsin-linked retinitis pigmentosa (RP) is the most common form of autosomal dominant RP, an inherited retinal degeneration, in which rod degeneration is followed by secondary cone loss leading to loss of vision and blindness. The overall objective of this work was to develop an optimized gene replacement therapy, delivering the rhodopsin gene for rhodopsin- linked RP and establish whether secondary cone loss can be delayed. A fast-acting single mutant serotype 8 self-complementary adeno-associated virus vector was produced containing the human rhodopsin promoter and the human rhodopsin coding sequence. In vivo studies in rhodopsin knockout mouse showed that the vector administration led to widespread and robust expression of the transgene. Subretinal injection of the vector into three-week pups of rhodopsin knockout mice with cones expressing green fluorescent protein showed restoration of rod-derived electroretinogram (ERG) responses, and preservation of cone- driven ERG responses three months after injection. Similarly, the longitudinal follow-up with confocal scanning ophthalmoscopy found preservation of fluorescent cones up to three months after injection. Overall, these data provided evidence that the designed vector resulted in significant benefit to rod photoreceptors as well as in delay in secondary cone degeneration and built a basis for future use of this vector on dominant models of RP.

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31

Wärnmark, Anette. "Molecular mechanisms of gene activation by nuclear receptors and their associated coregulators /." Stockholm : [Karolinska Univ. Press], 2001. http://diss.kib.ki.se/2001/91-7349-032-6/.

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32

Bockstael, Olivier. "Evaluation of gene transfer strategies using recombinant adeno-associated viruses for Parkinson's disease cell and gene therapy." Doctoral thesis, Universite Libre de Bruxelles, 2010. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210010.

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La maladie de Parkinson se caractérise entre autres par une dégénérescence progressive des neurones dopaminergiques de la substance noire pars compacta (SNpc) qui innervent le striatum. Cette dégénération entraîne une baisse de la sécrétion de dopamine dans le striatum qui est responsable de la majorité des symptômes moteurs de la maladie de Parkinson. Plusieurs approches ont été étudiées pour le traitement de la maladie de Parkinson :i) restaurer une synthèse de dopamine dans le striatum par une greffe striatale de neurones dopaminergique ou par un transfert striatal de gènes impliqués dans la synthèse de la dopamine ;ii) protéger et stimuler les neurones dopaminergiques survivants dans la substance noire pars compacta des patients ;iii) corriger les déséquilibres de la boucle motrice engendrés par la baisse de stimulation dopaminergique du striatum ;iv) stimuler et recruter des progéniteurs cérébraux pour les faire se différencier en neurones dopaminergiques dans le striatum. Toutes ces approches thérapeutiques peuvent impliquer des transferts de gènes.

Les vecteurs dérivés des virus adéno-associés (rAAV) constituent des outils de choix pour le transfert de gènes dans les tissus cérébraux. Par ailleurs, de nombreuses applications nécessitent une régulation de l’expression du transgène. Nous disposons au laboratoire d’un vecteur rAAV inductible à la tétracycline (rAAV-TetON).

Nous décrivons dans ce travail :

i) le comportement du vecteur rAAV dérivé du sérotype 1 d’AAV utilisant la cassette d’expression TetON (rAAV2/1-TetON) comparé à celui du rAAV2/1 utilisant un promoteur constitutif pour l’expression du transgène (rAAV2/1-pCMV) dans le striatum et le mésencéphale (contenant la substance noire). A l’aide d’un vecteur rAAV2/1-TetON exprimant le GDNF, nous montrons que nous pouvons moduler le niveau d’expression du transgène dans le striatum par la dose d’inducteur administré aux animaux. Par ailleurs, nous montrons que le rAAV2/1-TetON présente dans le striatum une efficacité de transduction moindre que le rAAV2/1-pCMV mais qu’il présente un profil de biosécurité supérieur au rAAV2/1-pCMV car il limite fortement l’expression du transgène hors du striatum. De plus, le rAAV2/1-TetON n’entraîne pas de recrutement de lymphocytes T ni d’activation de la microglie dans le striatum. Lorsqu’il est injecté dans le mésencéphale, le vecteur rAAV2/1-TetON, contrairement au rAAV2/1-pCMV présente une expression préférentielle dans les neurones dopaminergiques de la SNpc et de l’aire tégmentale ventrale (VTA).

ii) le comportement des vecteurs rAAV2/1-pCMV et scAAV2/1-pCMV (vecteur « self-complémentaire » permettant une expression du transgène indépendamment de la synthèse du second brin du génome viral) dans la région neurogénique de la zone sous-ventriculaire (ZSV). Nous avons montré que les vecteurs rAAV2/1 infectent efficacement la ZSV et s’y expriment rapidement. Les vecteurs scAAV2/1 s’expriment plus rapidement dans la ZSV que les vecteurs rAAV2/1 (expression maximum à 24h et 48h, respectivement). De plus, les vecteurs rAAV2/1 présentent une efficacité de transfection importante pour les progéniteurs neuraux en prolifération (cellules C, transient amplifying progenitors) et les neuroblastes en migration (cellules A) mais pas pour les cellules souches neurales (cellules B). Nous observons, par ailleurs, que les rAAV2/1 induisent une baisse transitoire de la prolifération de la ZSV. Cet effet est indépendant de l’expression du génome et dépend donc probablement de la capside virale de nos vecteurs. De plus, cette baisse de prolifération n’induit pas d’apoptose. A long terme, nous observons des cellules exprimant le transgène dans la zone granulaire du bulbe olfactif, indiquant que la transduction des progéniteurs de la ZSV n’interfère pas avec leurs capacités de migration et de différenciation.

iii) l’efficacité de différents sérotypes de rAAV pour le transfert de gènes dans les cellules progénitrices neurales (NPC) in vitro. Nous avons montré que les rAAV peuvent transduire des NPC mais que l’efficacité spécifique des différents sérotypes testés varie en fonction de la région du cerveau fœtal et de l’espèce dont les NPC sont issues. Par ailleurs, les rAAV induisent une réduction drastique de la prolifération des cultures de NPC dépendante du sérotype de rAAV utilisé mais pas de l’origine fœtale des NPC ou de l’espèce dont elles sont issues.

Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished

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33

Kulis, Michael D. "Islet neogenesis associated protein-related protein from gene to folded protein /." Available online, Georgia Institute of Technology, 2006, 2006. http://etd.gatech.edu/theses/available/etd-01112006-195113/.

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Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2006.
Shuker, Suzanne, Committee Chair ; Doyle, Donald, Committee Member ; Orville, Allen, Committee Member ; Barry, Bridgette, Committee Member ; McCarty, Nael, Committee Member.

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Kulis, Michael D. Jr. "Islet Neogenesis Associated Protein-Related Protein: From Gene to Folded Protein." Diss., Georgia Institute of Technology, 2006. http://hdl.handle.net/1853/10436.

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Type 1 diabetes is the direct result of an autoimmune attack on the pancreatic islet cells. The islets contain b cells, which are the only type of cell capable of supplying insulin in the human body. The destruction of these cells leaves the diabetic to rely on exogenous insulin to maintain a normal blood sugar level. Insulin therapy allows the diabetic to deal with the symptoms of the disease, but does nothing for the underlying condition. In order to truly cure the disease, the strategy is to replenish the b cells in the diabetic. Islet neogenesis associated protein (INGAP) has been shown to regenerate islet cells and reverse experimentally-induced diabetes in animal models. The INGAP pentadecapeptide is a 15 amino acid peptide from INGAP with comparable activity to the full-length protein. This 15-mer is undergoing clinical trials for treating diabetes. The overall goal of the project described in this work is to determine the structure of the INGAP pentadecapeptide for use in structure-based drug design of non-peptide mimics of the 15-mer. The first set of experiments in the present work directly examined the 15-mer in solution using NMR. No stable structure of the small peptide was found. The second set of experiments involved a homolog of INGAP, called INGAP-related protein, or INGAPrP. INGAPrP was recombinantly produced in E. coli and subsequently purified and refolded. Refolding of INGAPrP was verified by a 1H-15N HSQC experiment. CD experiments supported the NMR study, indicating helical content in INGAPrP. The folded nature of the protein will allow for the three-dimensional structure of INGAPrP to be determined. The protein structure will show the fold of the 15-mer within the full-length protein. This information will be valuable for the ultimate goal of producing structural mimics of the INGAP pentadecapeptide. Non-peptide mimics should have better oral bioavailability and longer half-lives in vivo.

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Borge, Kaja Sverdrup, Malin Melin, Patricio Rivera, Stein Istre Thoresen, Matthew Thomas Webster, Euler Henrik von, Kerstin Lindblad-Toh, and Frode Lingaas. "The ESR1 gene is associated with risk for canine mammary tumours." Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-200351.

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Background: The limited within-breed genetic heterogeneity and an enrichment of disease-predisposing alleles have made the dog a very suitable model for the identification of genes associated with risk for specific diseases. Canine mammary cancer is an example of such a disease. However, the underlying inherited risk factors for canine mammary tumours (CMTs) are still largely unknown. In this study, 52 single nucleotide polymorphisms (SNPs) in ten human cancer-associated genes were genotyped in two different datasets in order to identify genes/alleles associated with the development of CMTs. The first dataset consisted of English Springer Spaniel (ESS) CMT cases and controls. ESS is a dog breed known to be at increased risk of developing CMTs. In the second dataset, dogs from breeds known to have a high frequency of CMTs were compared to dogs from breeds with a lower occurrence of these tumours. Results: We found significant associations to CMT for SNPs and haplotypes in the estrogen receptor 1 (ESR1) gene in the ESS material (best P-Bonf = 0.021). A large number of SNPs, among them several SNPs in ESR1, showed significantly different allele frequencies between the high and low risk breed groups (best P-Bonf = 8.8E-32, best P-BPerm = 0.076). Conclusions: The identification of CMT-associated SNPs in ESR1 in two independent datasets suggests that this gene might be involved in CMT development. These findings also support that CMT may serve as a good model for human breast cancer research.

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Daniels, Jan Peter. "Nuclear architecture and gene expression-associated protein families in trypanosoma brucei." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509914.

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Hughes, Martin John Glenton. "A study of changes in gene expression associated with floral induction." Thesis, University of Nottingham, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.280454.

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Goodfellow, H. A. I. "Notch target gene regulation by chromatin associated factors and Ecdysone signalling." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599502.

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In this thesis I have identified several chromatin associated proteins and transcription factors that can regulate. Notch target gene expression and suggested models of how they may function during transcription regulation of the Notch pathway. First, I have shown that a Histone chaperone protein, Asf1, is involved in Notch target gene repression. Based on data that Asf1 recruited by binding to components of the Su(H) repressor complex and that Asf1 exists in a timer with Histone H3/H4, a model was formulated in which Asf1 brings Histone dimers to form new nucleosides on Notch target genes to aid in repression. Second, a screen for potential chromatin associated proteins involved in Notch signalling was performed. Several chromatin related genes were found to genetically interact with the Notch pathway. Four of the best candidate genes were studied further with direct effects on Notch target genes shown. One of these genes was taiman, the co-activator of the Ecdysone receptor, which is part of the steroid signalling pathway in Drosophila. Further work on taiman revealed it was expressed in the wing disc but its role in regulation of Notch remains unclear. Third, the role of Ecdysone signalling in Notch target gene regulation was investigated further. A series of in vivo experiments were performed where Ecdysone signalling levels were manipulated by altering the activity of the Ecdysone receptor. Changes in Ecdysone signalling were able to regulate the expression of three Notch target genes in two different tissues. For some genes a synergistic response in expression was observed when both Notch and Ecdysone pathway were activated. Furthermore, one of the primary Ecdysone targets, the Broad complex, was also shown to affect Notch target gene expression, leading to model where both the Ecdysone receptor and the Broad isoforms may co-operate on the promoters of Notch target genes to regulate their temporal expression.

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39

Okuchi, Yoshihisa. "Identification of Aging-Associated Gene Expression Signatures That Precede Intestinal Tumorigenesis." Kyoto University, 2016. http://hdl.handle.net/2433/217738.

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40

Wang, Ling, Zhi Q. Yao, Jonathan P. Moorman, Yanji Xu, and Shunbin Ning. "Gene Expression Profiling Identifies IRF4-associated Molecular Signatures in Hematological Malignancies." Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etsu-works/6538.

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The lymphocyte-specific transcription factor Interferon (IFN) Regulatory Factor 4 (IRF4) is implicated in certain types of lymphoid and myeloid malignancies. However, the molecular mechanisms underlying its interactions with these malignancies are largely unknown. In this study, we have first profiled molecular signatures associated with IRF4 expression in associated cancers, by analyzing existing gene expression profiling datasets. Our results show that IRF4 is overexpressed in melanoma, in addition to previously reported contexts including leukemia, myeloma, and lymphoma, and that IRF4 is associated with a unique gene expression pattern in each context. A pool of important genes involved in B-cell development, oncogenesis, cell cycle regulation, and cell death including BATF, LIMD1, CFLAR, PIM2, and CCND2 are common signatures associated with IRF4 in non-Hodgkin B cell lymphomas. We confirmed the correlation of IRF4 with LIMD1 and CFLAR in a panel of cell lines derived from lymphomas. Moreover, we profiled the IRF4 transcriptome in the context of EBV latent infection, and confirmed several genes including IFI27, IFI44, GBP1, and ARHGAP18, as well as CFLAR as novel targets for IRF4. These results provide valuable information for understanding the IRF4 regulatory network, and improve our knowledge of the unique roles of IRF4 in different hematological malignancies.

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Xu, Dan. "Cellular Immunity in Recombinant Adeno-Associated Virus Vector Mediated Gene Therapy." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1313504203.

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Pachhain, Sudhan. "Analysis of gene expression associated with drug-induced hyperthermia in rat." Bowling Green State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1562330027757666.

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Miyamoto, Yoshihiro. "Endothelial Nitric Oxide Synthase Gene Is Positively Associated With Essential Hypertension." Kyoto University, 1999. http://hdl.handle.net/2433/182280.

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Sabi, Essa. "Characterisation of ITGB3 and ITGA2B gene defects associated with Glanzmann thrombasthenia." Thesis, University of Sheffield, 2016. http://etheses.whiterose.ac.uk/13584/.

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Glanzmann thrombasthenia (GT) is a recessively inherited bleeding disorder caused by quantitative and, or, qualitative deficiencies of the platelet integrin αIIbβ3, which binds fibrinogen to mediate platelet aggregation at sites of vascular injury. The α- and β-subunits of αIIbβ3 are encoded by ITGA2B and ITGB3 respectively, and many genetic defects resulting in reduced expression or dysfunction of αIIbβ3 have been described. A previous survey of UK GT patients that was carried out by our group identified 14 uncharacterised nonsynonymous alterations in ITGA2B and ITGB3 that predicted amino acid substitutions in different domains of αIIb and β3. This study used combined in silico and in vitro approaches to confirm the pathogenicity of 13 of these alterations; eight ITGB3 variants predicting p.Trp11Arg, p.Pro189Ser, p.Glu200Lys, p.Trp264Leu, p.Ser317Phe, p.Cys547Trp, p.Cys554Arg and p.Ile665Thr substitutions in β3 and five ITGA2B variants predicting p.Asp396Asn, p.Leu492Pro, p.Ile596Thr, p.Asn670Lys and p.Glu698Asp substitutions in αIIb. With the exception of the β3_p.Glu200Lys and αIIb_p.Glu698Asp variants, in silico analysis predicted all variants to be pathogenic. Compared to cells expressing wild-type (WT) αIIbβ3, there was an almost complete absence of surface αIIbβ3 in cells expressing the p.Trp11Arg, p.Pro189Ser, Trp264Leu and Ser317Phe β3 variants (p<0.0001). In contrast, the β3_p.IIe665Thr variant was expressed at similar levels to WT, but showed reduced ability to bind an antibody that is specific for the active conformation of the receptor, PAC1 (p<0.01) and also fibrinogen (p<0.05), while the β3_p.Glu200Lys variant does not appear to cause dysfunction to αIIbβ3. Interestingly, cells expressing the p.Cys547Trp and p.Cys554Arg β3 variants showed moderate reductions in surface expression of αIIbβ3 (p<0.0001) that exhibited spontaneous activation (p<0.0001;p<0.001). The majority of the substitutions in β3 resulted in greater than 90% reductions (p<0.0001) in membrane expression of αvβ3 with the exception of the p.Glu200Lys and p.Pro189Ser substitutions which resulted in 78% (p<0.0001) and 21% (p<0.001) reductions in membrane expression of αvβ3, respectively. There was a severe reduction in membrane αIIbβ3 on cells expressing the p.Asp396Asn, the p.Leu492Pro and the p.Ile596Thr αIIb variants (p<0.0001) while the p.Asn670Lys αIIb was expressed at similar levels to wild-type αIIb. Interestingly, the p.Leu492Pro and p.Asn670Lys variants showed reduced ability to bind PAC1 (p<0.0001;p<0.01) and fibrinogen (p<0.0001;p<0.01). The c.2094G>T transversion in ITGA2B, predicted to cause a p.Glu698Asp substitution in αIIb, was associated with a ii splicing defect, resulting in the deletion of exon 20 from the ITGA2B RNA , and the loss of αIIbβ3 expression. These findings confirm the pathogenicity and demonstrate the underlying mechanisms associated with GT for the majority of the variants studied. Interestingly, while the β3_p.Glu200Lys variant does not appear to cause αIIbβ3 dysfunction, it does result in a reduction in αvβ3 (vitronectin) receptor expression, though it remains unknown how this defect results in GT.

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Reynolds, Paul Andrew. "Localization of a novel t(1;7) translocation associated with Wilms' tumour." Thesis, University of Bristol, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388159.

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Lauramore, Amanda K. "Retinal cell tropism of adeno-associated viral (aav) vector serotypes." [Gainesville, Fla.] : University of Florida, 2004. http://purl.fcla.edu/fcla/etd/UFE0005301.

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Thesis (M.S.)--University of Florida, 2004.
Typescript. Title from title page of source document. Document formatted into pages; contains 71 pages. Includes Vita. Includes bibliographical references.

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Pokiniewski, Katie Ann. "Understanding the cellular mechanism of Adeno-Associated Virus genome stabilization." Diss., Temple University Libraries, 2016. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/385837.

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Microbiology and Immunology
Ph.D.
The Adeno-Associated Virus(AAV) is a small, single stranded DNA virus that has been developed as a gene transfer vector. Early clinical trials using recombinant AAV vectors (rAAV) have identified the following concerns that need to be addressed in order to increase efficiency of these vectors. It has since been determined that AAV vector efficiency decreases due to the following mechanisms: ineffective endocytosis, endosomal degradation, inefficient trafficking, and the need to convert from a single-stranded AAV genome to a transcriptional active double-stranded form. The purpose of this study is to elucidate mechanisms that help stabilize the AAV genome in order to make it a more efficient vector for gene therapy. Previously, there have been studies using fluorescent labeling to track the movement of AAV into the nucleus. An integral part of AAV genomic stability may be the obstacles it encounters in the cytoplasm prior to entering the nucleus. Previous studies on improving AAV transduction have focused primarily on the nucleus. The study will hopefully shed light on the hurdles AAV encounters as it moves through the cytoplasm. Thus, this project has designed and utilized a new system for specifically tracking the status of AAV genomes in the cytoplasm as well as in the nucleus. This project utilizes a novel dual luciferase reporter system to track the movement of AAV particles from the cytoplasm into the nucleus to elucidate mechanisms that could contribute to the stabilization of the AAV genome. The novel dual reporter system is comprised of a single-stranded vector containing two different types of secreted luciferases: Cypridina Luciferase and Gaussia Luciferase. Cypridina Luciferase is placed under the control of a nuclear promoter and therefore it is expressed only in the nucleus. The second, Gaussia Luciferase, is under the control of a cytoplasmic promoter that will only be expressed in the cytoplasm upon the presence of T7 RNA polymerase. Using this dual reporter luciferase system along with RT qPCR quantification in a Hek293 cell line expressing the T7 RNA polymerase, demonstrated that genomes are present in the cytoplasm at 18 and 24 hours post infection. The second part of this study is using the dual reporter system to understand the trafficking patterns of rAAV and looking at ways to enhance transduction. One method could be administering rAAV vectors in conjunction with a drug; this approach may help overcome some of these cellular barriers encountered during infection as well as help stabilize the genome. Cidofovir (CDV) is a monophosphate nucleotide analogue that competitively inhibits the incorporation of deoxycytidine triphosphate into viral DNA via viral DNA polymerase. In vitro, CDV actively inhibits a number of DNA viruses including herpes viruses, adenovirus, polyomavirus, papillomavirus, and poxviruses. Cidofovir has already been approved by the Food and Drug Administration (FDA) for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). The effects of CDV on small DNA viruses that lack their own viral DNA polymerase, like AAV, has not been documented. Results have demonstrated that CDV is able to increase single-stranded rAAV transgene expression in the nucleus by 2 to 5 fold, depending on the cell type and concentration, in vitro, using both rAAV2 and rAAV8 luciferase reporter vectors. These results have been able to replicated using other reporter vectors: rAAV2-LacZ reporter, rAAV2-GFP, rAAV2-hAAT, and a rAAV8-GFP in vitro. Results have shown a dose-dependent increase in rAAV genomes with CDV pretreatment in HelaS3 cells via Southern Blot. Also southern blot analysis of cells pretreated with CDV then infected with rAAV revealed no difference in the amount of vector present between 0 and 2 hours post infection, suggesting CDV does not enhance viral entry but that CDV may enhance at steps downstream of viral entry. Using RNA sequencing and Ingenuity software analysis of HelaS3 cells pretreated with CDV, an increase in several genes of interest including those involved in the mechanism of viral exit were observed. These genes include Actin and vacuolar proteins, these molecules are involved in and associated with endosomal sorting complexes as well as required for transport inside the cell. This finding along with southern blot data supports the theory that CDV may enhance rAAV trafficking since we observed that CDV pretreatment enhances viral accumulation of rAAV vectors in both the cytoplasm and nucleus 24 hours post-infection. Also utilizing the dual luciferase reporter system an increase in transgene expression present with CDV pretreatment compared to PBS in both the cytoplasm and nucleus was observed suggesting that CDV may enhance with rAAV trafficking. These results taken together demonstrate that this dual reporter system is a powerful tool for understanding and improving rAAV trafficking. Also drugs like CDV can greatly contribute to the understanding of rAAV trafficking, and eventually lead to the development of novel strategies to increase overall efficiency of AAV transduction.
Temple University--Theses

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48

Asimakopoulos, Fotios A. "Molecular analysis of chromosome 20q deletions associated with myeloproliferative disorders and myelodysplastic syndromes." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388490.

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49

Erickson, Sarah. "Using Unnatural Amino Acid Incorporation to Modify and Manipulate Adeno-Associated Virus:." Thesis, Boston College, 2020. http://hdl.handle.net/2345/bc-ir:108955.

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Thesis advisor: Eranthie Weerapana
Adeno-Associated Virus (AAV) has been developed into a powerful therapeutic tool - in the last ten years it has acted as a gene-delivery vehicle in several approved therapeutics and many more therapeutics on trial. Despite extensive research, gaps in our understanding of AAV’s infectious cycle still exist, and further development is needed for the creation of improved gene therapy vectors. Technology to incorporate Unnatural Amino Acids (UAAs) into the AAV capsid has recently been developed, and could aid in both furthering our understanding of AAV’s biology and in the therapeutic advancement of AAV. In this work, we demonstrate how the functionalization of the AAV capsid using UAA incorporation can advance our control over the AAV capsid and aid in probing and manipulating AAV biology. We describe our use UAA incorporation to place a bio-orthogonal reactive handle into AAV’s capsid followed by functionalization with a targeting moiety and demonstrate the unprecedented amount of control that UAA incorporation provides in the creation of a functional virus conjugate. We are able to control both the precise placement and the stoichiometry of the targeting moiety on the AAV capsid, providing a platform that, for the first time, can undergo rigorous optimization analogous to that which medicinal chemists put small molecules through. We also describe the creation of a new platform to site-specifically modify the AAV capsid using cysteine incorporation, a technique that retains the ability to site-specifically modify the capsid as UAA incorporation does, but does not require the excess machinery that UAA incorporation requires. Next we discuss the incorporation of a photocaging amino acid, NBK, into the AAV capsid. Using NBK, we were able to effectively block AAV’s primary binding interaction with Heparan Sulfate Proteoglycan (HSPG) and control the timing of AAV infection using light to chemically remove the photo-protecting group. While photocaging the HSPG interaction is only a proof of concept, it demonstrates the remarkable amount of control that UAA incorporation affords, and lends insight to what could be accomplished using the functionalities that can be placed on the AAV capsid with UAAs
Thesis (PhD) — Boston College, 2020
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

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50

Krause, Lauren Kendall. "Gene Expression patterns in High-Altitude Pulmonary Edema: A Gene Microway Analysis." Yale University, 2008. http://ymtdl.med.yale.edu/theses/available/etd-08152007-111828/.

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Multiple modulating genes and environmental factors have been implicated in the pathogenesis of high-altitude pulmonary edema (HAPE). However, at the present time, there exists an incomplete understanding of the molecular mechanisms and pathways which underlie constitutional susceptibility. Genome-wide measurements of gene expression in peripheral blood mononuclear cells (PBMCs) were performed using microarray technology. Comparison of gene expression profiles of HAPE-susceptible and resistant individuals resulted in the identification of several previously undescribed candidate genes. RhoA and Rho-kinase (ROCK), regulators of vascular smooth muscle contraction, were differentially regulated in the HAPE-susceptible cohort, as compared to both HAPE-resistant patients with acute mountain sickness (AMS+) and healthy controls (p=0.0014; p=0.0020). Furthermore, biological pathways involving RhoA and Rho-kinase were strongly upregulated in subjects with HAPE. These findings represent the first description of the RhoA/Rho-kinase signaling pathway in HAPE. Currently, few pharmacologic therapies have been demonstrated to be effective in the prevention and treatment of HAPE. The results of this study provide early evidence that Fasudil, a selective Rho-kinase inhibitor, may represent a novel therapeutic intervention effective in the prevention and/or treatment of high-altitude pulmonary edema.

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Dissertations / Theses on the topic 'Associated gene'

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