The importance of the liver in contributing to growth processes is well established. However, the mechanisms by which it participates in these processes have remained elusive. One of the major obstacles to the identification and characterization of these mechanisms is the complexity of the growth process itself. This obstacle can be reduced by consideration of a more defined process: the role of the liver in mediating the effects of growth hormone. It has recently been demonstrated that growth hormone stimulates the hepatic mRNA content of two closely related members of the serine antiprotease family, Spi 1 and Spi 2. This proposal focuses on the participation of these proteins in the control of growth processes. The initial goal of this project will be the purification and in vitro characterization of Spi 1 and Spi 2 proteins. The genes encoding these proteins have been cloned and will be expressed from chimeric plasmids in the bacterium E. coli. This expression system will allow the purification of each protein free from contamination by the other so that specific antisera can be produced. The mature proteins can then be individually purified from serum. Characterization of the purified proteins will include determination of their spectra of protease inhibitory activities and examination of their structures. Purified Spi 1 and Spi 2 proteins will be used to identify their physiological targets. A variety of approaches will be taken to this problem, however, the initial step will be to identify tissue or serum proteins with affinity for Spi 1 or Spi 2 proteins. The specificity and nature of the interactions between Spi 1 or Spi 2 proteins and these proteins will then be addressed. Most importantly, the binding of Spi 1 or Spi 2 proteins to the putative targets will be examined for characteristics of a serine protease- protease inhibitor reaction. This will allow binding proteins which are most likely to be targets for Spi 1 and Spi 2 to be chosen for purification and subsequent study.
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| Schwarzenberg, S J; Sharp, H L (1990) Pathogenesis of alpha 1-antitrypsin deficiency-associated liver disease, 1990. J Pediatr Gastroenterol Nutr 10:5-12 |
