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Investigating regulators that control gene expression in cardiovascular diseases and links to metabolic dysfunction
1.Analyse roles for Brn-3a and Brn-3b in adult hearts in response to stress/injury: This will investigate the complex relationship of Brn-3a and Brn-3b affect survival of cardiomyocytes following injury such as myocardial infarction since increased Brn-3b can cooperate with p53 to enhance cell death whilst Brn-3a inhibits p53 mediated apoptosis so may protect cardiomyocyte after injury. To investigate this, we will mouse models to test effects of Brn-3a and Brn-3b in controlling cardiomyocyte fate in response to acute (coronary artery ligation) or chronic stress (AngII infusion or aortic banding). We will also analyse expression/function during cardiac remodelling/regeneration using zebrafish cryoinjury model. 2.Investigate potential roles for altered gene expression in congenital heart abnormalities: This research is based on observations that reciprocal expression for Brn-3a and Brn-3b in developing mouse heart is linked to repression of Brn-3b by Brn-3a in cardiomyocytes. As such, loss of Brn-3a results in increased Brn-3b in the developing heart which is linked with gene expression and functional changes are different gestation ages that may contribute to death of Brn-3a KO mutants within 0.5 day after birth. Future studies will aim to study the complex relationship between these regulators in the developing heart and using conditional KO mutants. 3. Investigating potential compensatory roles of Brn-3a and Brn-3b in the heart:Our early studies showed that loss of both Brn-3a and Brn-3b (Brn-3a/Brn-3b KO) causes early embryonic lethality in mice (E8.5) where targeting both Brn-3a and Brn-3b (double MO) in zebrafish embryos caused cardiac malformation. Therefore future studies will aim to analyse roles for Brn-3a and Brn-3b during cardiac development using conditional KO mouse models and transgenic zebrafish models (generated usingCrispR/cas 9 gene editing). 4.Elucidate essential roles for Brn-3b in maintaining cardio-metabolic and vascular health: Potentially novel roles for Brn-3b in controlling metabolic processes have been identified by studying Brn-3a be KO mutant mice which develop increased body fat and hyperglycaemia and insulin resistance, associated with type II diabetes. Furthermore, Brn-3b was shown to regulate the glucose transporter, GLUT4. However these mice also develop vascular dysfunction at younger ages so we aim to investigate its potential roles in metabolic processes and links to vascular dysfunction.
5 Researchers
2 External Collaborators
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Status: Active
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