Haptoglobin is a plasma protein which binds free hemoglobin released by aged and injured red blood cells. It belongs to a group of plasma proteins-- positive acute phase reactants - whose synthesis is increased several-fold in response to acute infection, inflammation or injury. One biological function of haptoglobin is to prevent iron loss and kidney damage during hemolysis, a condition often related to hemolytic anemia in older people. In humans and mice, haptoglobin exhibits an age-dependent differential response to inflammation suggesting the existence of an age- related influence to gene expression. Haptoglobin also is reported to increase in healthy elderly people. Although the principal site of haptoglobin biosynthesis is the liver, it appears also to be synthesized in extra-hepatic tissues, such as brain, lung, and kidney, where it could have an important biological function(s) during inflammation and aging. In this application, molecular mechanisms of expression of human haptoglobin- luciferase chimeric genes in transfected hepatic and extra-hepatic cell lines modulated with inflammatory factors and hormones will be investigated. It will be of interest ot determine whether the same, or different, DNA sequence(s) in the human haptoglobin gene 5'flanking region is/(are) involved in regulation of haptoglobin-luciferase chimeric gene expression in hepatic and extra-hepatic fell lines. Haptoglobin-luciferase enzyme activities and mRNA levels, and endogenous haptoglobin protein and mRNA levels in transfected cells will be determined. Specific DNA sequence(s) which confer expression of haptoglobin-luciferase chimeric genes to extra-hepatic cells, or increased interleukin-6 inducibility to hepatic cells will be localized utilizing 5' deletion mutants, linker scanning mutants and point mutations. Attempts will be made to identify, isolate and characterize protein factor(s) that interact with DNA sequence(s). A better understanding of the regulation of human haptoglobin gene expression in response to inflammatory factors or hormones could help improve medical treatment of inflammatory diseases and kidney failure.
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