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Student research project 

Supervisor(s): Dr Anna Calkin and Dr Brian Drew

Identifying novel ways to inhibit the damage caused by excess lipids so we can prevent the onset of cardiometabolic disease (fatty liver disease, cardiovascular disease, diabetes).

Project summary

One is three Australians have elevated cholesterol levels and a similar number have elevated triglyceride levels. These excess lipids can be deposited in tissues such as the heart, liver and skeletal muscle where they have detrimental effects, promoting atherosclerosis, cardiac dysfunction, steatosis and insulin resistance. Moreover, through developments in technology, we are able to identify hundreds of other lipids, many of which have been shown to have pathological effects promoting the onset of cardiometabolic disease. These studies aim to identify novel pathways through which these lipids act, and determine whether they have therapeutic potential to prevent the onset of cardiometabolic disease.

We provide a novel approach to identify new pathways associated with lipid regulation. This approach is based on associating the genetic variability across 100 strains of mice with a given phenotype in these mice (1,2). Specifically, we have linked differences in hepatic protein expression in 100 strains of mice to changes in plasma and liver lipid levels. Excitingly, this approach has identified many new candidates, never before linked to lipid metabolism (3).

This project will involve validation of these identified candidates in liver cells and translation of these findings to mouse models.

  • In vitro studies will be performed in the human liver cell lines and will involve genetic manipulation to overexpress and inhibit a given target and assessment of effects on markers of lipid metabolism.
  • Preclinical studies will involve turning a candidate pathway on and off , followed by assessment of parameters including lipid levels and lipid signaling pathways, metabolic signaling and substrate metabolism as well as markers of metabolic disease including heart function, glucose tolerance. 

Related methods, skills or technologies

This project will expose you to numerous skills and technologies, including:

  • cloning
  • adenovirus
  • expression constructs
  • shRNA knockdown
  • cell culture (liver cell lines, primary liver cells, transfection, infection)
  • Assessment of lipid pathways
  • qPCR
  • Western blot
  • preclinical models (AAV transduction, metabolic assessment).

This project is suitable for a Honours or PhD student.

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References

  1. Bennett, et al.
    A high-resolution association mapping panel for the dissection of complex traits in mice
    Genome Research 2010;20(2):281–90
  2. Parks, et al.
    Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice
    Cell Metabolism 2013;17(1):141–52
  3. Parker, Calkin et al.
    An integrative systems genetic analysis of mammalian lipid metabolism
    Nature 2019;567(7747):187–93

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