There are two major long range goals for the research carried out in this laboratory. The first of these is to characterize at the biochemical and molecular level the terminal enzymes of the heme biosynthetic pathway and the second is to examine regulatory mechanisms of heme biosynthesis that exist in erythroid and non-erythroid cell types. An integral part of both of these goals is to understand at both a biochemical and cellular level the specific nature of two human porphyrias, variegate porphyria (VP) and erythropoietic protoporphyria (EPP), and the disease X-linked sideroblastic anemia. The current research proposal can be subdivided into three general areas; I) production and characterization of gene knockout and gene replacements in cultured mouse ES cells, II) production and initial characterization of the corresponding genetically modified mice, and III) characterization of mammalian ALA synthase. Our specific interests in establishing the porphyric cell and animal models are to gain an understanding of why humans possessing these disorders routinely exhibit variable penetrance, why symptomatic patients exhibit significantly different intensities of symptoms, and why clinically documented differences exist between male and female patients. Our interest in the X-linked sideroblastic anemia is to determine the effect of this disorder on normal erythropoiesis, and to see if the heterozygous female is compromised, and if the homozygous female is viable. The interest in characterization of ALA synthase is to understand at a biochemical level the nature of the enzymatic defects that one finds in X- linked sideroblastic anemia and to better understand this enzyme which is one of the key regulatory points in heme biosynthesis.
Showing the most recent 10 out of 33 publications
