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PhD by Research Programme (Funded Research Programme - Cross Cutting)

Employer
Global Academy Jobs
Location
Singapore
Closing date
Jan 31, 2017

Job Details

Research Project Title: Comparative Developmental Genomics of the Great Ape Heart: Evolutionary Roots of Human Heart Disease 

Source of Funding: R-SUG

Principal Investigator: Assistant Professor Irene Gallego Romero, LKCMedicine

Project Description:

Changes in gene regulation are likely to play an important role in speciation and adaptation. Although many studies have identified and dissected instances of regulatory changes with adaptive consequences in a broad set of species, examples in primates are much rarer, especially those where the underlying molecular mechanisms are fully understood. Comparative studies of regulatory mechanisms in primates are challenging due to the practical and ethical constraints on genetic experimentation in apes — the closest living relatives to humans — and because of the very limited availability of tissue samples. Thus, most of our insights into gene regulation in these animals are primarily observational, in spite of their clear potential to inform our understanding of both human evolution and disease.

One such observation is the very different aetiology of heart disease in humans and all other great apes, which is associated with changes in cardiomyocyte and collagen fibre distribution in the myocardium. The evolutionary roots of this difference are unclear, but it is known that over 3,000 genes are differentially expressed in the hearts of humans and chimpanzees. Deciphering the gene regulatory mechanisms that underpin these differences could therefore provide novel insights into our understanding of this pathology – a leading cause of death worldwide, both in humans and captive apes. However, to fully dissect these traits it is fundamental that we move beyond the approaches that have characterised much comparative genomics research to date.

Induced pluripotent stem cell (iPSC) lines provide a tantalisingly flexible and powerful model to do so. Once established, iPSCs can be differentiated in vitro to terminal cell types such as cardiomyocytes with ease, allowing us to perform comparative studies of regulatory developmental pathways to identify inter-species differences that contribute to phenotypic differences at the organismal level.  Against this framework, this project has the following specific aims:

Aim 1: Establish induced pluripotent stem cell (iPSC) lines derived from 10 Bornean orang-utans (Pongo pygmaeus) in collaboration with the Singapore Zoo. These cell lines will complement an existing human and chimpanzee iPSC lines that we have previously generated to create a multispecies primate iPSC resource. High quality iPSC lines from orang-utans will greatly deepen our understanding of human and ape evolution, as they represent the most ancient living split within the great apes.

Aim 2: Dissect the interactions between cardiomyocytes and fibroblasts through cellular co-culture and 3D culture. Controlled observation of the interactions between these cell types is vital to understanding how cardiac fibroblasts contribute to pathogenic fibrotic remodelling of the heart in apes and humans.

Aim 3: Identify species-specific spatiotemporal differences in gene expression and regulation during development and in the adult tissue, and the regulatory mechanisms that underpin them. By developing novel analytical approaches to combine multiple genomic data sets, we will gain insights into the evolutionary causes of human heart disease and uncover regulatory pathways that influence it.

If you have questions regarding this project, please email the Principal Investigator, Assistant Professor Irene Gallego Romero, at igr@ntu.edu.sg

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