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dc.contributor.advisorBaillie, Kenneth
dc.contributor.advisorDigard, Paul
dc.contributor.advisorRossi, Adriano
dc.contributor.authorParkinson, Nicholas J.
dc.date.accessioned2022-09-02T12:47:58Z
dc.date.available2022-09-02T12:47:58Z
dc.date.issued2022-09-02
dc.identifier.urihttps://hdl.handle.net/1842/39340
dc.identifier.urihttp://dx.doi.org/10.7488/era/2591
dc.description.abstractGenetics contribute substantially to the ability of the immune system to respond appropriately to a challenge. Consequently, many infectious and inflammatory diseases have a heritable component. As genome-wide association studies provide increasing data linking genetic variants to disease, we can leverage this information to gain insights into disease biology if we can elucidate the mechanisms underlying an observed association. Data-driven bioinformatic approaches, in vitro mechanistic studies and whole-organism approaches to study integrated pathophysiological systems provide complementary information to help establish causal links between specific variants and their effects on a target gene, and between that gene and disease pathogenesis. Cells of the mononuclear phagocyte system play key roles in regulation of innate and adaptive immune responses, either via secreted mediators or through direct cell-to-cell contacts. To advance understanding of how these regulatory processes, and genetic variations therein, shape the course of disease, I have combined experimental and bioinformatic approaches to explore novel genetic associations between genes for macrophage surface receptors and human disease. Specifically, functional follow-up of an association between adhesion G-protein-coupled receptor CD97 and severe influenza showed, using a mouse model, that deficiency of this receptor reduces the efficiency of the CD8+ T-lymphocyte response, a process critical to clearance of infected cells. Secondly, I addressed the question of how to identify causal variants in a disease-associated linkage disequilibrium block, for an association between macrophage regulatory receptor SIRPα and schizophrenia. To achieve this, I developed novel methodology for targeted locus screening using CRISPR/Cas9 mutagenesis, and identified a number of plausible causal regulatory variants that could affect expression of this receptor. Combining variant-level information with gene-level studies of disease pathophysiology can provide valuable insights into genetic causation of immune dys-regulation leading to disease, which may be harnessed for improved personalised disease risk prediction, or to identify therapeutically targetable pathways.en
dc.contributor.sponsorWellcome Trusten
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionParkinson N, Rodgers N, Fourman MH, Wang B, Zechner M, Swets MC, Millar J, Law A, Russell CD, Baillie JK et al. 2020. Dynamic data-driven meta-analysis for prioritisation of host genes implicated in COVID-19. Sci entific reports 10.en
dc.relation.hasversionPairo-Castineira E, Clohisey S, Klaric L, Bretherick A, Rawlik K, Parkinson N, Pasko D, Walker S, Richmond A, Fourman MH, . . . Baillie JK. 2020. Genetic mechanisms of critical illness in Covid-19. Nature doi: 10.1038/ s41586-020-03065-yen
dc.relation.hasversionClohisey S, Parkinson N, Wang B, Bertin N, Wise H, Tomoiu A, The Fan tom Consortium, Summers KM, Hendry RW, Carninci P . . . Baillie JK. 2020. Comprehensive characterisation of transcriptional activity during influenza A virus infection reveals biases in cap-snatching of host RNA sequences. Journal of virology doi: 10.1128/JVI.01720-19.en
dc.relation.hasversionLi B, Clohisey SM, Chia BS, Wang B, Cui A, Eisenhaure T, Schweitzer LD, Hoover P, Parkinson NJ, Nachshon . . . Baillie JK. 2020. Genome-wide CRISPR screen identifies host dependency factors for influenza A virus infection. Nature communications 11.en
dc.relation.hasversionNicholas Parkinson et al. “Dynamic data-driven meta-analysis for prioritisation of host genes implicated in COVID-19”. In: Scientific Reports 10.1 (2020), page 22303. DOI: 10.1038/s41598-020-79033-3en
dc.subjectmacrophagesen
dc.subjectbioinformaticsen
dc.subjectmononuclear phagocyte systemen
dc.subjectmouse modelsen
dc.subjectCRISPR/Cas9en
dc.subjectrisk predictionen
dc.titleFunctional genomics in the regulation of the immune responseen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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