Molecular pathogenesis and treatment of obesity/diabetes-associated heart disease: The insight into mechanisms and therapeutic potentials

Both the number of cases and the prevalence of obesity/diabetes are increasing globally. Cardiovascular complications are the leading causes of diabetes mortality. With the exception of vascular and valvular injuries, diabetic cardiomyopathy (DCM) is a distinct myocardial disease, which is characterised by abnormal cellular metabolism and defects in organelles function, leading to impaired cardiac function. Epidemiological studies have revealed increasing incidence of DCM in diabetic patients, featured by hypertrophy and diastolic dysfunction with consequential heart failure. Thus, elucidating molecular pathogenesis of DCM is pivotal for the discovery of potential therapeutic approaches.

Endoplasmic Reticulum (ER) and mitochondria both exhibit the key roles in maintaining intracellular lipid homeostasis. Lipid droplets can be protective by storing fatty acid as the energy fuel, but excessive lipids induce toxicity to the cells. Particularly, in obesity/diabetes, lipid overload and impaired lipid metabolism occur in the heart, leading to DCM and heart failure. Therefore, it is crucial to gain molecular and functional evidence that ER and mitochondrial regulation of lipid metabolism in the myocardium, which will provide new insights into therapeutic potential for preventing cardiac stenosis and heart failure.

In the proposed project, we aim to identify novel genes involved in ER and mitochondrial function; advance our understanding of their function in the heart using genetic modified models; elucidate novel molecular basis underlying impaired ER/mitochondria-induced cardiac dysfuntion; investigate the molecular basis whereby ER/mitochondria regulats lipid homeostasis in the heart; and provide new insights into the beneficial effects of preserved ER/mitochondrial function against DCM, as a means of ameliorating the onset and progression of heart failure in diabetes populations.

Training/techniques to be provided

This project will provide a comprehensive training for a PhD student in systematic and translational medicine with a wealth of animal work and molecular and cellular approaches: real-time PCR, western blot, histology, immunocytochemistry and immunofluorescence, informatics, RNA-Seq, Mass-spectrometry, ChIP assay, Luciferase assay, and sub-cloning; in vitro cell culture (primary heart cells and cell line): genetic engineering, stimulation, transfection; Animal work and assessments: genetic modified animal models, in vivo metabolic assessments (examining blood insulin, glucose and cholesterol, and measuring blood pressure), in vivo cardiac functional study (echocardiography and electrocardiography), in vivo gene therapy.

Entry requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second-class honours UG degree (or equivalent) in a related subject, with or without a Master degree depending on experience. Candidates with experience in any molecular and cellular techniques or animal work or biochemistry or medicine or pharmacology with an interest in diabetes and heart diseases are encouraged to apply. 

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How To Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

On the online application form select PhD Cardiovascular Sciences.