Homozygous PIZZa1-antitrypsin (aAT) deficiency is the most common genetic cause of liver disease in children and of emphysema in adults. This deficiency is associated with a misfolding by functionally active aATZ molecule which is retained in the endoplasmic reticulum (ER) rather than secreted into the blood and body fluids. Lung injury is due to the decrease in a1AT molecules available in the lung to inhibit neutrophil elastases. Liver injury is due to the hepatotoxic effect of the misfolded a1AT molecule retained in the ER. The investigator has observed that a subgroup of PIZZ individuals may be more susceptible to liver injury by virtue of co-inherited variants in the quality control apparatus of the ER which is responsible for recognition and degradation of misfolded proteins. The investigator has also found that the proteasome plays a key role in the degradation of a1ATZ. More recent studies have shown that the classical autophagic response also plays a role in response to, and degradation of a1-ATZ. In addition, the investigator has evidence which suggests that exogenous chemical chaperones can at least partially reverse the folding defect of a1-ATZ and at least on of these, 4-phenylbutyric acid, is an excellent candidate for chemoprophylaxis of both liver and lung disease in a1-AT-deficiency. In addition, the investigator has also observed that several inhibitors of carbohydrate processing, castanospermine and kifunensine, also mediate increased secretion of a1ATZ. Thus, in the renewal application, the investigator proposes to focus on the effects of chemical chaperones and inhibitors of carbohydrate processing on mutant a1-AT-deficient patients. The investigator also plans to continue the studies of proteolytic mechanisms which determine the fate of a1-ATZ in the ER and of specific, presumably protective, signal transduction pathways that are activated by the retention of a1-ATZ in the ER. Lastly, the investigator proposes to determine whether there are tissue-specific differences in ER retention of a1-ATZ and the autophagic response in the lung and liver of PiZ mouse in vivo during homeostasis and inflammation.
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