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Student research project

Supervisor(s): Dr Alexander Pinto

Understanding the key drivers of cardiac fibrosis and how to target them.

Project summary

Fibrosis is a key contributor to the development of heart failure, a leading cause of death worldwide. Yet, there are no effective treatments to address fibrosis. Using state of the art single-cell omics we have recently discovered two critical new cell types — Fibroblast-Cilp (Fibro-Cilp) and Fibroblast-Thbs4 (Fibro-Thbs4; collectively Fibro-Cilp/Thbs4) — which emerge in the context of hypertension and are abundant in human and mouse hearts undergoing non-ischemic fibrosis. Fibro-Cilp/Thbs4 are the two most fibrogenic cell types of the heart. They are present in contexts of fibrosis which are not associated with ischemic injury, and thus differ to myofibroblasts, which emerge only in the context of ischemic injury.

Further building on this work, we have now pin-pointed the molecular drivers — called transcription factors (TFs) — that confer Fibro-Cilp/Thbs4 their fibrosis-causing phenotype. We are now at a stage where we wish to use in vitro models of Fibro-Cilp/Thbs4 to test:

  1. Which of these TFs are essential for Fibro-Cilp/Thbs4 development.
  2. Screen chemical libraries to identify antagonists of essential TFs.

Undertaking these two tasks is critical for developing new drugs to target Fibro-Cilp/Thbs4. However, in vitro models that precisely recapitulate the phenotypes of Fibro-Cilp/Thbs4 do not exist.This project will address this limitation by combining single-cell genomics, mechanobiology, and human and mouse genetics. The project will specifically test the hypothesis that by altering key cellular growth conditions that cell closely mirroring Fibro-Cilp/Thbs4 can be recapitulated. We will additionally test the capacity of in vitro-generated Fibro-Cilp/Thbs4 model can be miniatures for high-throughput drug screening.

Related methods, skills or technologies

The project is suitable for an Honours or PhD student and will involve applying various skills and techniques, including:

  • analytical methods (inc. 2D and 3D microscopy, flow cytometry, single-cell transcriptomics).
  • data science
  • high-throughput drug screening
  • in vitro models of cardiovascular disease
  • single-cell genomics.

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