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Title: The systematic identification and characterisation of genes differentially expressed in the early development of pressure-induced left ventricular hypertrophy
Author: Mahadeva, Harin
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2001
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available