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Title: Molecular and metabolomic mechanisms affecting growth in children born small
Author: Butcher, Imogen
ISNI:       0000 0004 5352 9979
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2014
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Small for gestational age (SGA) is defined as a birth weight or crown to heel length of -2 or more standard deviation scores. It is associated with increased risk of mortality and morbidity in the neonatal period and also has long term effects including an increased risk of developing type II diabetes, high blood pressure and cardiovascular disease later in life. Infants born SGA usually show catch-up growth within the first few years of life. However in the UK, ~1500 SGA children each year remain small and the reason for this is not understood. The aim of this work was to investigate the molecular mechanisms known to contribute to post-natal growth and also to develop a metabolomic profile in children born SGA. Skin biopsies were obtained with local ethical approval from prepubertal healthy children and children born SGA. Cell turnover (proliferation and apoptosis) and growth hormone (GH) and insulin like growth factor-I (IGF-I) signalling in fibroblasts was assessed and the metabolomic profile in these groups was determined. During this study, blood samples and auxological data were also obtained in children born SGA with catch-up growth and children born SGA without catch-up growth. Cell counting and bromodeoxyuridine incorporation demonstrated that proliferation was comparable between SGA cells compared to control cells under basal, GH (200ng/ml) and a combination of GH (20ng/ml) plus IGF-I (10ng/ml) stimulated conditions. However, IGF-I (100ng/ml) stimulated proliferation was significantly reduced in the SGA cells compared to control cells (p<0.001). Basal apoptosis was significantly increased in SGA cells compared to control cells (p<0.005). GH and IGF-I reduced apoptosis in SGA cells; however, the level of apoptosis remained significantly higher in SGA cells compared to control cells (p<0.005). GH and IGF-I signalling pathways in SGA cells and control cells were assessed by western blotting, immunoprecipitation and phosphoarray. GH (200ng/ml) induced phosphorylation of Stat5b was significantly reduced in SGA cells compared to control cells (p<0.001). IGF-I (100ng/ml) activation of Akt was altered, as Akt2 was activated in SGA cells but not in controls cells (p<0.001). Metabolomic profiling of SGA cells revealed alterations in respiration, up-regulation of the urea cycle, altered fatty acid metabolism and altered cell signalling compared to control cells. The data presented in this thesis increases the understanding of the molecular mechanisms that affect growth in children born small, and has identified a metabolomic profile of SGA children without catch-up growth. This work may lead to new, more specific therapy for these individuals, and metabolomics may enable the identification of infants who do not show post-natal catch-up growth much earlier, leading to earlier commencement of recombinant human GH.
Supervisor: Clayton, Peter; Westwood, Melissa Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available