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Characterising extreme innate immune response phenotypes informative for disease using a functional genomics approach (360G-Wellcome-204969_Z_16_Z)

<p>The overall aim is to define and characterise extreme innate immune response phenotypes in order to gain insights into the functional alleles driving such differences between individuals; biological consequences in terms of gene regulation, cellular function and disease; and opportunities for therapeutic intervention. Key goals are (1) to analyse existing transcriptomic and expression quantitative trait mapping datasets for primary monocytes activated by lipopolysaccharide (endotoxin) or interferon-gamma from a large cohort of healthy volunteers to identify extreme responders (aggregated and gene level), using genetics to resolve functional alleles then validate and establish functional consequences including through chemical probes; (2) to use genome editing to conduct high-throughput screens in human induced pluripotent stem cell derived monocytes complementing the genetic data; (3) to define key nodal genes and networks for drug target discovery and prioritisation; and (4) to characterise prioritised genes and functional alleles modulating gene transcription and epigenetic regulation relevant to disease. Anticipated outcomes are improved understanding of pathophysiology in immune-mediated disease notably sepsis; exemplars to the field of how to establish mechanism for functional alleles involving regulatory genetic variants; improved interpretation of genome-wide association studies; novel nodal points involving TLR and related pathways as drug targets; and better drug target prioritisation.</p>

£1,575,666

30 Nov 2016

Grant details
Amount Awarded 1575666
Applicant Surname Knight
Approval Committee Science Interview Panel
Award Date 2016-11-30T00:00:00+00:00
Financial Year 2016/17
Grant Programme: Title Investigator Award in Science
Internal ID 204969/Z/16/Z
Lead Applicant Prof Julian Knight
Planned Dates: End Date 2022-10-02T00:00:00+00:00
Planned Dates: Start Date 2017-10-02T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East
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