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Title: KIAA1109 is differentially expressed in whole blood early after myocardial infarction in humans and is required for vascular integrity in zebrafish
Author: Solaymani-Kohal, Sara
ISNI:       0000 0004 2732 4099
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2013
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Background: I aimed to identify genes that are differentially expressed in whole blood in patients following myocardial infarction (MI) and assess these functionally in zebrafish. Methods: We recruited patients admitted with acute coronary syndromes (MI or unstable angina). We performed whole genome microarrays on RNA extracted from whole blood at 1, 3, 7, 30 and 90d post admission, comparing the whole blood transcriptome of patients with MI with unstable angina. I then assessed the role of one such candidate (KIAA1109) in zebrafish cardiovascular development. Results: From > 54000 genes assessed, 39 genes were significantly differentially expressed in peripheral blood at 1d post MI, returning to baseline at later time points. 27 of these 39, have clear zebrafish homologues, 14 with protein similarity >50%. 9 genes were up regulated in MI, while 5 were down regulated, including a gene of unknown function; KIAA1109. I therefore knocked down KIAA1109 in developing zebrafish and assessed its role in vascular development. I also performed a microarray comparing whole embryo RNA from 36h post fertilization KIAA1109 morphants with control to assess the transcriptional effect of loss of function of KIAA1109. KIAA1109 morphant Fli1:GFP/Gata1:dsRED transgenic zebrafish were examined by confocal microscopy for evidence of vascular abnormalities. KIAA1109 morphants developed cerebral haemorrhage (3dpf control 10%, vs. KIAA1109 morphants 50% p < 0.05). KIAA1109 knockdown induced a significant decrease in the number of endothelial cells (EC) in the forebrain of KIAA1109 morphants (47±4 vs. 73±6 in control) and hindbrain (53±4 morphants vs. 95±7 in control) at 2dpf. There was a significant decrease in the number of EC nuclei in the cardinal vein of KIAA1109 morphants (68±6 vs. 101±8 in control). The phenotype of KIAA1109 knockdown was rescued by administration of the VEGF inducer GS4012. The microarray of total RNA from 36hpf KIAA1109 morphants identified genes that were significantly down regulated by KIAA1109 knockdown such as protocadherin 1 gamma 2, involved in the cadherin-signalling pathway and ligand of numb-protein X1, involved in the NOTCH pathway. Conclusion: KIAA1109 is significantly down regulated in human whole blood 1d post MI. Knockdown of KIAA1109 induces severe cerebral haemorrhage in developing zebrafish and significant differential expression of important developmental genes. Functional and transcriptomic assessment in zebrafish suggests KIAA1109 is required for vascular integrity and may be a therapeutic target post MI.
Supervisor: Chico, Timothy J. A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available