Research Project
6871860
DESCRIPTION (provided by applicant): The heme oxygenase isoenzymes HO-1 (the inducible form) and HO-2 (the constitutive form) have been attributed to many functions: The reaction substrates are unique in that they are pro-oxidants or signaling molecules. Using several models, we have shown that altered expression of HO-1 and HO-2 modifies reactive iron content in cells and tissues. More recent evidence suggests that HO proteins can alter HO-1 promoter activation and that HO-1 can migrate to the nucleus. It is speculated that the byproducts of the enzymatic reaction of HO explain its various effects on cellular function however, this has not been demonstrated systematically or consistently because many studies did not evaluate whether overexpression or disruption of the HO genes was associated with a reliable change in HO activity and a consistent alteration of these reaction products. We hypothesize that: 1) increased protein expression of HO-1 or HO-2 modifies the transcription of HO-1 mRNA and protein and thereby is a feedback mechanism for the regulation of HO-1 expression. 2) nuclear migration of HO-1 is an important signaling event that impacts on cell proliferation and apoptosis. 3) increased nuclear migration of HO-1 in the lungs of neonatal mice is a protective mechanism against oxidative injury. Therefore our specific aims are: 1) to characterize the effects of HO protein on HO-1 transcriptional activation. 2) to document HO-1 nuclear migration and evaluate the resultant effects on cell proliferation and apoptosis. 3) to determine whether there are maturational differences in the nuclear localization of HO-1 in vivo and whether this promotes tolerance to hyperoxia. A better understanding of the mechanism by which HO mediates its actions may help dictate therapeutic strategies to enhance or suppress HO effects.
