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Professor Nabeel Affara

Abstract:

The DOHaD (Developmental Origins of Health and Disease) hypothesis was initially proposed by Barker (2001) on the basis of extensive epidemiological studies linking low birth weight with increased incidence of the metabolic syndrome (e.g. coronary heart disease, hypertension, type 2 diabetes, stroke) in later life. It proposes that intrauterine and early postnatal exposures alter (programme) the metabolic state of offspring; subsequent postnatal mismatch of the programmed metabolic response to nutritional environment can lead to disease (Gluckman and Hanson, 2004).       There is evidence that epigenetic mechanisms are involved in programming events at candidate loci, but few studies have used comprehensive genome-wide analyses or integrated different layers of epigenetic control (DNA and histone modifications) with transcriptional outcome.        This project uses a well established rat model of metabolic syndrome found in humans (Vickers et al., 2000). The model demonstrates complex interactions between diet, metabolism and immune system function, likely involving coordination from the central nervous system This animal model offers the opportunity to take an integrated genomic approach to elucidate the correlations between altered gene expression levels and defined epigenetic modifications of DNA and chromatin that are associated with early life exposures and subsequent development of the metabolic syndrome phenotype. The project will employ RNA seq and ChIPseq approaches (based on high throughput sequencing) on liver, white adipose tissue and muscle to identify differential gene expression and epigenetic modifications in between offspring of normally and undernourished pregnancies.

References:

  1. Barker DJ (2001). Med. Health Care Philos. 4: 31–35  
  2. Gluckman PD and Hanson MA (2004). Science 305: 1733–1736  
  3. Vickers MH, Breier BH, Cutfield WS, Hofman PL, and Gluckman PD (2000). Am. J. Physiol. Endocrinol. Metab. 279: E83–87

Second supervisor:

Dr Carole Sargent