14 results on '"Uusi-Mäkelä, Meri"'
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2. Intelectin 3 is dispensable for resistance against a mycobacterial infection in zebrafish (Danio rerio)
- Author
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Ojanen, Markus J. T., Uusi-Mäkelä, Meri I. E., Harjula, Sanna-Kaisa E., Saralahti, Anni K., Oksanen, Kaisa E., Kähkönen, Niklas, Määttä, Juha A. E., Hytönen, Vesa P., Pesu, Marko, and Rämet, Mika
- Published
- 2019
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3. NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease
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Uusimaa, Johanna, Kaarteenaho, Riitta, Paakkola, Teija, Tuominen, Hannu, Karjalainen, Minna K., Nadaf, Javad, Varilo, Teppo, Uusi-Mäkelä, Meri, Suo-Palosaari, Maria, Pietilä, Ilkka, Hiltunen, Anniina E., Ruddock, Lloyd, Alanen, Heli, Biterova, Ekaterina, Miinalainen, Ilkka, Salminen, Annamari, Soininen, Raija, Manninen, Aki, Sormunen, Raija, Kaakinen, Mika, Vuolteenaho, Reetta, Herva, Riitta, Vieira, Päivi, Dunder, Teija, Kokkonen, Hannaleena, Moilanen, Jukka S., Rantala, Heikki, Nogee, Lawrence M., Majewski, Jacek, Rämet, Mika, Hallman, Mikko, and Hinttala, Reetta
- Published
- 2018
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4. Characterization of the innate immune response to Streptococcus pneumoniae infection in zebrafish
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Saralahti, Anni K., primary, Harjula, Sanna-Kaisa E., additional, Rantapero, Tommi, additional, Uusi-Mäkelä, Meri I. E., additional, Kaasinen, Mikko, additional, Junno, Maiju, additional, Piippo, Hannaleena, additional, Nykter, Matti, additional, Lohi, Olli, additional, Rounioja, Samuli, additional, Parikka, Mataleena, additional, and Rämet, Mika, additional
- Published
- 2023
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5. Zebrafish as a Model for Human Genetic and Infectious Diseases
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Uusi-Mäkelä, Meri, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, and Tampere University
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tuberkuloosi ,tuberculosis ,zebra fish ,malliorganismi ,Lääketieteen ja biotieteiden tohtoriohjelma - Doctoral Programme in Medicine and Life Sciences ,FINCA ,seeprakala ,CRISPR-Cas9 ,zebrafish ,model organism - Abstract
Yhteisen evoluutiohistoriamme vuoksi osa ihmisen geeneistä voidaan tunnistaa meille läheisistä sukua olevissa eläimissä. Jaamme suuren osan perimästämme simpanssin (Pan troglodytes) ja hiiren (Mus musculus), mutta kenties yllättäen myös seeprakalan (Danio rerio) kanssa. Huolimatta sen vedenalaiseen elämään sopivista piirteistä, osa seeprakalan geeneistä, fysiologiasta ja mikropatologiasta muistuttavat ihmisen vastaavia ominaisuuksia. Sukulaislajien biologinen vastaavuus mahdollistaa oman biologiamme mallintamisen jopa hyvin alkukantaisina pidetyissä lajeissa, ja on olennainen osa lääketieteellistä tutkimusta. Joissain tapauksissa voimme näet hyödyntää jopa hyvin kaukaista sukulaislajia, kunhan voimme osoittaa tutkimamme geenin tai signalointireitin vastaavuuden lajien välillä. Tässä väitöstutkimuksessa olemme käyttäneet seeprakalaa mallina ihmisen geneettisessä tutkimuksessa neljässä projektissa, jotka keskittyvät kehitysbiologiseen genetiikkaan ja tautigenetiikkaan. Näissä projekteissa olemme hyödyntäneet geenihiljennystä ja mutageneesiä seeprakalan geenien tutkimisessa. Ensimmäisessä tutkimuksessa pyrimme selvittämään CRISPR-Cas9 (clustered regularly interspaces short palindromic repeats, CRISPR associated 9) mutageneesin tehokkuudessa havaitsemiemme erojen perimmäistä syytä. Havaitsimme tutkimuksessamme eroja mutageneesin in vivo- ja in vitro -tehokkuudessa geenien välillä seeprakalan poikasessa. Päättelimme, että tämä saattaisi johtua DNA:n erilaisesta pakkausmekanismeista in vivo. Emme kuitenkaan havainneet merkittävää korrelaatiota epigeneettisten tekijöiden ja CRISPR-Cas9 mutageneesin tehokkuuden välillä. Tuloksemme kuitenkin osoittivat, että mutageneesin tehokkuudessa in vivo ja in vitro havaitut erot ovat geenikohtaisia, joten havaitut erot voivat osin johtua DNA:n pakkausmekanismeista. Toisessa projektissa mallinsimme seeprakalassa ihmisessä hiljattain tunnistettua geneettistä FINCA-sairautta (engl. fibrosis, neurodegeneration and cerebral angiomatosis). FINCA ilmenee varhaislapsuudessa ja johtaa potilaan kuolemaan ennen kahden vuoden ikää. Sairauden syyksi on tunnistettu mutaatio geenissä nimeltä NHLRC2. Hiiressä mutaatiot vastaavassa geenissä johtavat elinkyvyttömyyteen varhaisissa kehitysvaiheissa, minkä vuoksi hiiri ei sovellu sairauden mallintamiseen. Vastaavan nhlrc2 geenin hiljennys seeprakalassa johti kalanpoikasissa muutoksiin keskiaivojen solukossa. Tuloksen perusteella seeprakalamallissa havaitut muutokset vastaavat osin potilaissa havaittuja muutoksia. Tuloksemme osaltaan vahvistavat, että mutaatiot NHLRC2 geenissä aiheuttavat FINCA-sairauden. Samaa hiljennysmenetelmää käyttäen tutkimme myös intelectin 1-geenin merkitystä kaloissa, joiden intelectin 3-geeni oli mutatoitu toimimattomaksi. Intelektiinit ovat proteiineja, jotka osallistuvat bakteerien tunnistukseen elimistössä. Havaitsimme matalalla annoksella infektoiduissa kaloissa intelectin3-geenin ilmentymistason olevan merkittävästi koholla. Emme kuitenkaan havainneet muutoksia intelectin3 poistogeenisissä seeprakaloissa. Päättelimme, että samanlaisen ilmentymiskinetiikkansa vuoksi intelectin1 voisi kompensoida intelectin3 puuttumista mutatoiduissa kaloissa ja näin estää mutaation aiheuttamien muutoksen havaitsemisen. intelectin1-geenin hiljentäminen mutatoiduissa kaloissa ei kuitenkaan johtanut havaittaviin muutoksiin seeprakalan poikasissa tehdyssä infektiokokeessa. Viimeisessä projektissa tutkimme pycard-geenin merkitystä mykobakteeri- infektiossa. pycard koodaa proteiinia, joka toimii osana inflammasomikompleksia, minkä on havaittu osallistuvan hankinnaisen immuunivasteen säätelyyn. CRISPR- Cas9 -menetelmällä tuotetuissa poistogeenisissä kaloissa havaittiin heikennyt vaste selviämiskokeissa. Tämän lisäksi poistogeenisillä kaloilla havaittiin suurempi bakteerimäärä elimistössä ja niissä ilmenneet granuloomat olivat suurempia. RNA- sekvensoinnin avulla osoitimme kalan puolustussolujen geenien ilmentymisessä useita muutoksia, joiden perusteella kaloilla on muuttunut vaste mykobakteeri- infektiolle. Projekteissa hyödynsimme monipuolisesti seeprakalaa ihmisen tautimallinnuksessa. Intelektiinien ja nhlrc2-geenin tutkimuksessa geenihiljennyksellä saatiin aikaan transkriptin lähes täydellinen eliminointi, vaikka intelektiinien kohdalla tämä ei johtanutkaan fenotyypissä havaittaviin muutoksiin. Inflammasomin pycard- geenin mutatoinnilla saatiin aikaan malli, jonka avulla voimme hahmottaa yhä tarkemmin geenin merkitystä mykobakteerin aiheuttamassa infektiossa. Tuloksemme ovat osoitus seeprakalan soveltuvuudesta ihmisen genetiikan tutkimuksessa. Due to our shared evolution, humans share parts of their genetics with related animals. We share most of our genes with the chimpanzee (Pan troglodytes) and with mouse (Mus musculus), but perhaps surprisingly also with zebrafish (Danio rerio). Despite its aquatic lifestyle and fishy looks, zebrafish shares most of its genes and several parts of its physiology and micropathology with human. These biological similarities of related species are invaluable for medicine, as they allow us to study our own biology through evolutionary homology in even species which are considered very primitive in phylogenetic terms. The selection of a model species should be based on ethics as well as the question at hand. In some cases, we can use a very distant species, provided that we can show the conservation of the gene or pathway biology between us and the model organism. In this thesis we have used zebrafish as a model for human genetics in four projects with focus on developmental and disease genetics. In each project, we employed gene silencing or mutagenesis to study zebrafish genes. In our first project, we set out to study the differences observed in the efficiency of the CRISPR-Cas9 (clustered regularly interspaces short palindromic repeats, CRISPR associated 9) mutagenesis system. We observed differences between in vitro and in vivo efficiencies of mutagenesis between genes in larval zebrafish. This led us to consider if the efficiency of mutagenesis was determined by DNA packaging in vivo. Our results did not reveal strong correlation between epigenetic factors and CRISRP-Cas9 efficiency. However, our results indicate mutagenesis functions differently between genes independent of in vitro functionality, suggesting an influence from DNA packaging. In the second project, we generated a zebrafish model for a newly identified human genetic disease, FINCA (fibrosis, neurodegeneration and cerebral angiomatosis). FINCA manifests in early childhood and leads to death of affected children before the age of two and is a result of a mutation in a gene NHLRC2. Mutations in mouse Nhlrc2 lead to early lethality, which significantly hampers its applicability in studying FINCA. Silencing of nhlrc2 in zebrafish lead to alterations in integrity of brain cells in zebrafish larvae based on the analysis of TEM images in comparison to controls, suggesting it replicates some parts of the phenotype of the patients. Our results support notion that the loss of NHLRC2 is the cause of the FINCA disease. With the same gene silencing technology, we analysed the effect of intelectin 1 gene on intelectin 3 mutated zebrafish. Intelectins are a family of proteins involved in recognition of bacteria in cells. Primarily, intelectin 3 was found to be upregulated in mycobacterial infection in our microarray data of adult zebrafish. We failed to see a phenotype in intelectin 3 mutated zebrafish, which lead us to consider if intelectin 1, due to similar expression kinetics, could be compensating for its loss, masking the phenotype of the mutants. However, simultaneous silencing and knockout of intelectin 1 and intelectin 3, respectively, did not result in a phenotype in larval zebrafish in mycobacterial infection. In the last project we set out to determine the role of the gene pycard in mycobacterial infection. pycard codes an adaptor protein of the inflammasome complex, which has also been indicated to play a role in adaptive immune response. Results showed that CRISPR-Cas9 generated pycard knockout zebrafish present decreased survival in mycobacterial infection. In addition, they present alteration in bacterial burden and granuloma size. RNA-sequencing analysis of the kidney transcriptome of the fish suggest multiple changes in transcription, which makes the knockout fish susceptible to mycobacterial infection. Our model suggests inflammasome signalling has a central role in orchestrating host’s defence and neutrophil function during mycobacterial infection. In these projects we explored the versatile applications of zebrafish in modelling human diseases. With the study of intelectins and nhlrc2, gene silencing led to near total elimination of the transcript, even though with intelectins this did not cause detectable changes in the phenotype. With mutagenesis of inflammasome adaptor gene pycard, we were able to generate a model suitable for generating a detailed understanding on its function in mycobacterial infection. Our results demonstrate the utility of the zebrafish in modelling human genetics.
- Published
- 2022
6. Integrating fish models in tuberculosis vaccine development
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Saralahti, Anni K., Uusi-Mäkelä, Meri I.E., Niskanen, Mirja T., Rämet, Mika, Tampere University, BioMediTech, and Clinical Medicine
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3111 Biomedicine - Abstract
Tuberculosis is a chronic infection by Mycobacterium tuberculosis that results in over 1.5 million deaths worldwide each year. Currently, there is only one vaccine against tuberculosis, the Bacillus Calmette-Guérin (BCG) vaccine. Despite widespread vaccination programmes, over 10 million new M. tuberculosis infections are diagnosed yearly, with almost half a million cases caused by antibiotic-resistant strains. Novel vaccination strategies concentrate mainly on replacing BCG or boosting its efficacy and depend on animal models that accurately recapitulate the human disease. However, efforts to produce new vaccines against an M. tuberculosis infection have encountered several challenges, including the complexity of M. tuberculosis pathogenesis and limited knowledge of the protective immune responses. The preclinical evaluation of novel tuberculosis vaccine candidates is also hampered by the lack of an appropriate animal model that could accurately predict the protective effect of vaccines in humans. Here, we review the role of zebrafish (Danio rerio) and other fish models in the development of novel vaccines against tuberculosis and discuss how these models complement the more traditional mammalian models of tuberculosis. publishedVersion
- Published
- 2020
7. Syöpäimmunologian tulevaisuus : immunologisesti kylmä syöpäkudos kuumaksi
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Uusi-Mäkelä, Meri, Rämet, Mika, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, and Tampere University
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Biolääketieteet - Biomedicine ,Syöpätaudit - Cancers ,Lääketieteen bioteknologia - Medical biotechnology - Published
- 2020
8. Integrating fish models in tuberculosis vaccine development
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Saralahti, Anni K., primary, Uusi-Mäkelä, Meri I. E., additional, Niskanen, Mirja T., additional, and Rämet, Mika, additional
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- 2020
- Full Text
- View/download PDF
9. Intelectin 3 is dispensable for resistance against a mycobacterial infection in zebrafish (Danio rerio)
- Author
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Ojanen, Markus, Uusi-Mäkelä, Meri, Harjula, Sanna-Kaisa, Saralahti, Anni, Oksanen, Kaisa, Kähkönen, Niklas, Määttä, Juha, Hytönen, Vesa, Pesu, Marko, Rämet, Mika, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, and Tampere University
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Biolääketieteet – Biomedicine ,Lääketieteen bioteknologia - Medical biotechnology ,Genetic engineering ,Tuberculosis ,Infection ,Transcriptomics ,Biokemia, solu- ja molekyylibiologia - Biochemistry, cell and molecular biology - Published
- 2019
10. Molecular features of steroid-binding antidins and their use for assaying serum progesterone
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Agrawal, Nitin, primary, Lehtonen, Soili I., additional, Uusi-Mäkelä, Meri, additional, Jain, Purvi, additional, Viitala, Sari, additional, Määttä, Juha A. E., additional, Kähkönen, Niklas, additional, Azizi, Latifeh, additional, Riihimäki, Tiina A., additional, Kulomaa, Markku S., additional, Johnson, Mark S., additional, Hytönen, Vesa P., additional, and Airenne, Tomi T., additional
- Published
- 2019
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11. Hijacking Host Angiogenesis to Drive Mycobacterial Growth
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Uusi-Mäkelä, Meri, primary and Rämet, Mika, additional
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- 2018
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12. Chromatin accessibility is associated with CRISPR-Cas9 efficiency in the zebrafish (Danio rerio)
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Uusi-Mäkelä, Meri I. E., primary, Barker, Harlan R., additional, Bäuerlein, Carina A., additional, Häkkinen, Tomi, additional, Nykter, Matti, additional, and Rämet, Mika, additional
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- 2018
- Full Text
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13. Capture of hydrocortisone binding avidins from a combinatorial library based on chicken avidin scaffold
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Uusi-Mäkelä, Meri, BioMediTech - BioMediTech, and University of Tampere
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Biokemia - Biochemistry - Published
- 2015
14. <italic>NHLRC2</italic> variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease.
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Uusimaa, Johanna, Kaarteenaho, Riitta, Paakkola, Teija, Tuominen, Hannu, Karjalainen, Minna K., Nadaf, Javad, Varilo, Teppo, Uusi-Mäkelä, Meri, Suo-Palosaari, Maria, Pietilä, Ilkka, Hiltunen, Anniina E., Ruddock, Lloyd, Alanen, Heli, Biterova, Ekaterina, Miinalainen, Ilkka, Salminen, Annamari, Soininen, Raija, Manninen, Aki, Sormunen, Raija, and Kaakinen, Mika
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NEURODEGENERATION ,FIBROSIS ,ANGIOMATOSIS - Abstract
A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver. A whole-exome sequencing of the two unrelated families with the affected children revealed the transmission of two heterozygous variants in the NHL repeat-containing protein 2 (NHLRC2); an amino acid substitution p.Asp148Tyr and a frameshift 2-bp deletion p.Arg201GlyfsTer6. NHLRC2 is highly conserved and expressed in multiple organs and its function is unknown. It contains a thioredoxin-like domain; however, an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity. In patient-derived fibroblasts, NHLRC2 levels were low, and only p.Asp148Tyr was expressed. Therefore, the allele with the frameshift deletion is likely non-functional. Development of the
Nhlrc2 null mouse strain stalled before the morula stage. Morpholino knockdown ofnhlrc2 in zebrafish embryos affected the integrity of cells in the midbrain region. This is the first description of a fatal, early-onset disease; we have named it FINCA disease based on the combination of pathological features that include fibrosis, neurodegeneration, and cerebral angiomatosis. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
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