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Crispr/Cas9 and microRNA-based Precision Medicine for Determining the Pathogenesis of Cardiovascular Disease

Project Description

Diabetes predisposes subjects to cardiovascular disease (CVD) (e.g., atherosclerosis and heart disease), the second main cause of death in the UK. The development of CVD is closely associated with the dysregulation on lipoprotein protein metabolism and energy metabolism in the heart. One key mechanism is the overproduction of apolipoprotein B (apoB), the major structure protein in very low density lipoprotein (VLDL) particle, acting as a lipid transporter to shuttle hepatic lipids to peripheral tissues and contributing to the onset of atherosclerosis. Moreover, expression profile of non-coding small RNAs (e.g., microR-378) is significantly altered in myocardial infarction which couples with key genes in mitochondrial energy metabolism (e.g., ERRand PPARto modulate cardiac mitochondrial integrity and ATP production. Therefore, the overarching goal of this project is to determine the regulatory role of the microRNA-378 and ERR in cardiac pathological remodelling and arterial integrity in the high fat diet induced insulin resistant state. Two specific aims will be pursued to fulfil the goal.

Aim 1: To generate an apoB knockout cell model using the cutting-edge gene editing technology, Crispr/Cas9 system, and determine the impact of apoB on insulin sensitivity, VLDL metabolism and atherosclerosis development.

Aim 2: To establish the regulatory role of the miR-378 and ERR on cardiac mitochondrial integrity, fatty acid -oxidation and pathological remodelling of cardiomyocytes.

This project is significant because it will provide evidence for the pharmaceutical designs to specifically manipulate the functional activity of ERR using synthetic miR-378 mimics/inhibitors in the prevention and treatment of CVD.

Specific skills/experience required by applicants:

Experience on small laboratory animals (e.g. mouse and rat) and general molecular biological techniques (e.g. Immunoblotting analysis and Q-PCR) are essential for this position.

Funding Notes

Only UK and EU students are eligible to apply. Information on eligibility criteria is available from DfE: View Website

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