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Showing 61 to 64 of 64 (0.026 seconds)Spelling suggestions: "subject:"isoforms A""
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EVALUATION OF AMINOINDOLE CARBOXAMIDES AND TRIAZINES AS POTENTIAL ANTI-AGGREGATION AGENTS OF PROTEIN MISFOLDING DISEASESEduardo Ramirez (18436542) 06 May 2024 (has links)
<p dir="ltr">My research projects focuses on the dual targeting of small molecules to abrogate aberrant α-syn, tau (2N4R), and p-tau (1N4R) aggregation and to reduce the spread of AD and related dementias. Not very many drug discovery programs focus on the specific isoforms of the tau protein. We established two series of compounds: aminoindole compounds connected by a carboxamide and triazine compounds connected by a triazine linker. Using biophysical methods we evaluated the effectiveness of both series of compounds in decreasing the amount of misfolded α-syn and tau protein in order to explore their anti-aggregation potential.</p><p><br></p>
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Telomerase and its reverse transcriptase subunit TERT : identification and oestrogenic modulation of telomerase transcription in two aquatic test species - European Purple Sea Urchin (Paracentrotus Lividus) and Rainbow Trout (Oncorhynchus Mykiss)Brannan, Katla Jorundsdottir January 2012 (has links)
A plethora of naturally-produced steroid hormones, or artificial homologues of them, are being introduced into the aquatic and terrestrial environments each year. Two examples of these are the natural oestrogen 17ï¢-oestradiol (E2) and the oestrogen receptor antagonist, Bisphenol A (BPA), both of which target the ribonucleoprotein telomerase through upregulation of its telomerase reverse transcriptase component, TERT. The main objectives of this study were firstly to isolate and characterize the actual mRNA sequence for the telomerase catalytic subuninit, Tert, in rainbow trout (Oncorhynchus mykiss) (Walbaum, 1792) and European purple sea urchin (Paracentrotus lividus) (Lamarck, 1816), with the aim of developing qPCR assays for the amplification and quantification of Tert. Further objectives were to use these assays in controlled exposure studies to establish whether and to what extent the aforementioned chemicals regulate Tert transcription and by doing so further understand the mechanism of Telomerase gene expression and the extent to which environmental oestrogen can interfere. The initial step of sequence characterization and assay devlopment was successful in the case of rainbow trout where two possible splice variants of Tert mRNA are identified, omTertShort and omTertLong. Two qPCR assays were developed for the relative quantification of both of these splice variants in rainbow trout samples, the latter of these successfully amplifying its target in test samples. In order to demonstrate in vitro and in vivo modulation of telomerase activity and mRNA expression, early life-stages of rainbow trout and purple sea urchin, as well as rainbow trout hepatocytes, were exposed to a range of concentrations of E2 and BPA. Purple sea urchin embryos were exposed to 200, 20 and 2 ng E2/ml for 28 hours until they had reached the stage of pluteus larvaes. Rainbow trout embryos were exposed to 500, 20 and 0.1 ng E2/ml and 600 and 150 ng BPA/ml for 167 days from immediately after fertilization. Rainbow trout hepatocytes were exposed to 20 and 2 ng E2/ml for 48 hours. The results from this study show that telomerase activity as well as TERT mRNA expression can be significantly modulated by exposure to oestrogens and other oestrogenic chemicals. E2 concentrations as low as 20 ng/ml lead to an increase in telomerase activity early-life stages of purple sea urchin and upregulation in the transcription of Tert mRNA in unhatched rainbow trout embryos. BPA induced similar response (600 ng/ml) in hatched rainbow trout alevins larvae. Very high exposures to E2 (500 ng/ml) do however lead to downregulation of Tert mRNA in hatched alevins larvae. Differential regulatory response can be observed between different tissue types of 167 day old fry, with an upregulatory response observed at 0.1 ng E2/ml in liver and muscle tissues, but not in brain. Similarly, brain tissues were observed expressing significantly less mRNA than liver and muscle samples when exposed to BPA (150 ng/ml). It is evident that the previously observed link between environmental oestrogens and telomerase is also present in the two test species examined; purple sea urchin and rainbow trout.
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Micro RNA-Mediated regulation of the full-length and truncated isoforms of human neurotrophic tyrosine kinase receptor type 3 (NTRK 3)Guidi, Mònica 13 January 2009 (has links)
Neurotrophins and their receptors are key molecules in the development of thenervous system. Neurotrophin-3 binds preferentially to its high-affinity receptorNTRK3, which exists in two major isoforms in humans, the full-length kinaseactiveform (150 kDa) and a truncated non-catalytic form (50 kDa). The twovariants show different 3'UTR regions, indicating that they might be differentiallyregulated at the post-transcriptional level. In this work we explore howmicroRNAs take part in the regulation of full-length and truncated NTRK3,demonstrating that the two isoforms are targeted by different sets of microRNAs.We analyze the physiological consequences of the overexpression of some of theregulating microRNAs in human neuroblastoma cells. Finally, we providepreliminary evidence for a possible involvement of miR-124 - a microRNA with noputative target site in either NTRK3 isoform - in the control of the alternativespicing of NTRK3 through the downregulation of the splicing repressor PTBP1. / Las neurotrofinas y sus receptores constituyen una familia de factores crucialespara el desarrollo del sistema nervioso. La neurotrofina 3 ejerce su funciónprincipalmente a través de una unión de gran afinidad al receptor NTRK3, del cualse conocen dos isoformas principales, una larga de 150KDa con actividad de tipotirosina kinasa y una truncada de 50KDa sin dicha actividad. Estas dos isoformasno comparten la misma región 3'UTR, lo que sugiere la existencia de unaregulación postranscripcional diferente. En el presente trabajo se ha exploradocomo los microRNAs intervienen en la regulación de NTRK3, demostrando que lasdos isoformas son reguladas por diferentes miRNAs. Se han analizado lasconsecuencias fisiológicas de la sobrexpresión de dichos microRNAs utilizandocélulas de neuroblastoma. Finalmente, se ha estudiado la posible implicación delmicroRNA miR-124 en el control del splicing alternativo de NTRK3 a través de laregulación de represor de splicing PTBP1.
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Analysis of genetic variation in microrna-mediated regulation and the susceptibility to anxiety disordersMuiños Gimeno, Margarita 18 December 2009 (has links)
We have investigated genetic variation in microRNA-mediated regulation as a susceptibility factor for anxiety disorders following two different approaches. We first studied two isoforms of the candidate gene NTRK3 by re-sequencing its different 3'UTRs in patients with Panic (PD) and Obsessive Compulsive disorders (OCD) as well as controls. Two rare variants that altered microRNA-mediated regulation were identified in PD. Conversely, association of a common SNP with OCD hoarding subtype was found. Moreover, we have also studied a possible involvement of microRNAs in anxiety disorders. Consequently, we have analysed the genomic organisation and genetic variation of miRNA-containing regions to construct a panel of SNPs for association analysis. Case-control studies revealed several associations. However, it is worth remarking the associations of miR-22 and miR-488 with PD; two microRNAs for which functional assays and transcriptome analysis after microRNA overexpression showed significant repression of a subset of genes involved in physiological pathways linked to PD development. / Hem investigat la variació genètica a la regulació mediada per microRNAs com a factors de susceptibilitat pels trastorns d'ansietat seguint dues aproximacions diferents. Primer vam estudiar dues isoformes del gen candidat NTRK3 mitjançant la reseqüenciació dels seus diferents 3'UTRs a pacients de pànic (TP), a pacients amb trastorn obsessiu compulsiu (TOC) i a controls. Dues variants rares que alteren la regulació mediada per microRNAs foren identificades per TP. D'altra banda, es trobà associació d'un SNP comú amb el subtipus acumulador de TOC. A més, també hem estudiat la possible implicació dels microRNAs als trastorns d'ansietat. Conseqüentment, hem analitzat l'organització genòmica i la variació genètica a regions que contenen microRNAs per construir un panell d'SNPs per fer anàlisis d'associació. Els estudis cas-control van revelar algunes associacions. Tanmateix, val la pena destacar les associacions del miR-22 i el miR-488 amb TP; dos microRNAs pels quals assajos funcionals i anàlisis de transcriptoma després de la seva sobreexpressió han mostrat una repressió significativa d'un grup de gens implicats en vies fisiològiques lligades al desenvolupament del TP.
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