U534646.pdf (9.75 MB)
The systematic identification and characterisation of genes differentially expressed in the early development of pressure-induced left ventricular hypertrophy
thesisposted on 2014-12-15, 10:29 authored by Harin. Mahadeva
In this work, I developed a novel molecular indexing-based method for the systematic profiling of gene expression. It is technically simple and efficient at detecting differentially expressed genes, with a high sensitivity and low false-positive rate. The cascade hypothesis of LVH suggests that shortly after a pressure stimulus, key regulatory molecules are activated to initiate the events leading to cardiomyocyte hypertrophy. Using molecular indexing, I isolated seven genes that are differentially expressed in the left ventricle 4hrs after the induction of pressure-induced LVH by aortic coarctation in the rat. These include IkB, Xin, -filamin, muscle LIM, cardiac adriamycin responsive protein, myocyte-enriched calcineurin-interacting, protein-1, and a novel gene designated 1113a1. These genes have either previously not been studied in LVH or implicated in its early development. Their characteristics reinforce the concept of a re-induction of an embryonic gene program in LVH and suggest a link between molecular mechanisms involved in cardiogenesis and cardiomyocyte hypertrophy.;The full-length 1113a1 mRNA sequence was found to be 1.2Kb. It is expressed during embryogenesis and is highly striated muscle-specific in the adult. The putative protein (317aa) contains several interesting functional motifs and exhibits evolutionary conservation. Regulation of 1113a1 in in vitro models of hypertrophy and hypoxia suggests a stimulus-specificity of activation with involvement in different cellular stress responses, and supports recent evidence of a link between oxidative stress and hypertrophic signalling pathways. Over-expression studies suggest a potential role in hypertrophic rather than general cellular growth.
Date of award2001-01-01
Awarding institutionUniversity of Leicester