Investigating the Coordination of Growth, Metabolism, and the Cardiovascular System During Embryonic Development and its Impact on Adult Health and Disease

Abstract

Chronic metabolic and cardiovascular disorders display a U-shaped association with early life growth trajectory, with large- and small-for-gestational-age status correlating with elevated risk of metabolic and cardiovascular disease later in life. While this phenomenon has been replicated in human cohort studies across the globe, longitudinal in vivo models investigating early growth and the impact on adult health are currently lacking, particularly with regard to cardiac disease risk. Growth factor receptor bound protein 10 is a negative regulator of the insulin/IGF signalling pathway, the primary pathway involved in the coordination of growth and early development. Here, grb10a expression was transiently knocked down to assess the impact of acute upregulation of the insulin signalling pathway during development, and constitutively knocked out to determine aspects of the phenotype specifically associated with developmental remodelling. Grb10a knockdown was associated with elevated early growth and metabolic rate, which persisted into adulthood. This was coupled with a permanent remodelling of the transcriptome. Adult knockdown zebrafish were characterised by a leaner body with distinct skeletal and cardiac muscle hypertrophy. These characteristics were also seen during early development when grb10a expression was constitutively knocked out, recapitulating the knockdown phenotype. Growth trajectory and body shape during the larval and adult stages was significantly altered in the knockout zebrafish, which was not observed in the knockdown, indicating grb10a has an ongoing role in modulating growth throughout the life course of the organism. Growth velocity was dysregulated, oscillating around the WT growth velocity, indicating the presence of homeostatic mechanisms regulating late larval growth. Transcriptomic analysis showed significant increases in biological markers of metabolic, mitochondrial, and cardiac dysfunction as well as advanced biological ageing. This was coupled with reactive oxygen species accumulation and reduction in telomere length. Together, these results clearly demonstrate the importance of grb10a in the normal timing of growth, development, and biological age. Overall, this thesis presents an appropriate in vivo model for longitudinal study of the Developmental Origins of Health and Disease hypothesis, and successfully characterises a model in which growth, metabolism, and cardiac development are clearly linked.

Date of Award	9 Dec 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Peter Clayton (Supervisor), Adam Stevens (Supervisor), Adam Hurlstone (Supervisor) & Holly Shiels (Supervisor)