Molecular mechanisms responding to DNA damage and replication stress at the replication fork (360G-Wellcome-110014_Z_15_Z)

£250,000

There are two major strands to my proposed research. First, I aim to establish direct molecular connections between different DNA damage response (DDR) proteins linked to nephronophthisis-related ciliopathies (NPHP-RC). Second, I aim to understand how the DDR interfaces with other cellular pathways to drive morphological defects relevant to disease progression observed in a 3D kidney spheroid model system. To address the first aim, I will monitor genetic and protein interactions between DDR fact ors of interest sharing similar molecular functions and disease phenotype. This will determine if these factors collaborate in a common DDR pathway. To address the second aim, I will determine if key phenotypes of interest are observed concomitant with kidney spheroid morphology defects. Specifically, I will ask if apoptosis, senescence or epithelial-to-mesenchymal transition are elevated upon DDR activation, and probe the importance of these in spheroid dysfunction by genetic rescue experiments . In parallel, I will use unbiased genetic and proteomic screens to determine the major effectors of DDR proteins linked to NPHP, and validate these hits as causative of DDR-induced defects in spheroid assays. These parallel approaches will significantly expand our understanding of the molecular basis of the NPHP-RC phenotype associated with mutations in specific DDR proteins.

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Grant Details

Amount Awarded 250000
Applicant Surname Taylor
Approval Committee Basic Science Interview Committee
Award Date 2015-11-11T00:00:00+00:00
Financial Year 2015/16
Grant Programme: Title Sir Henry Wellcome Postdoctoral Fellowship
Internal ID 110014/Z/15/Z
Lead Applicant Dr Martin Taylor
Partnership Value 250000
Planned Dates: End Date 2019-02-15T00:00:00+00:00
Planned Dates: Start Date 2016-06-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Scotland
Sponsor(s) Prof John Rouse