The physiological stimuli of changing pressure and flow promote compensatory hypertrophy in several organ systems in humans and animals. Renal glomeruli in diabetes and left ventricular myocytes in hypertension display such post-mitotic tissue growth. While these result in initial adaptive benefits to the organism, fibrosis and loss of function of the organ eventually ensue, thereby leading directly to morbidity and mortality from these disease processes. Insulin-like growth factor I (IGF-I) is a peptide structurally and functionally very similar to insulin. IGF-I is less potent than insulin as a metabolic hormone but much more potent than insulin as a mitogenic agent. Unlike insulin, however, IGF-I protein is made in almost all organs, raising the possibility that it might function locally to control tissue growth. Our laboratory identified tissue-specific enhancement of IGF-I gene expression early in both these models of adaptive growth, suggesting that it participates in initiating the hypertrophic response in tissues no longer capable of cell division. We also identified differential regulation of a tissue-specific panel of IGF-binding proteins capable of restricting or promoting access of IGF-I to its receptor.
Current objectives are to: 1) identify the hormonal and physiological stimuli responsible for induction of the IGF-I growth factor axis in vivo and in vitro; 2) elucidate the mechanisms by which these factors regulate expression of the IGF-I and IGF binding protein genes; 3) define the structural and functional consequences of IGF-I overexpression in vivo and in vitro; and 4) determine if tissue-specific expression of IGF-I is necessary and/or sufficient to initiate hypertrophy. To achieve these aims, we combine physiological, molecular, and cell biological techniques and use both intact animal adenoviral expression systems and targeted cell culture for molecular analysis.
Adjunct Associate Professor, Department of Medicine
MD from New York University
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