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GloriaFerreira

Gloria Ferreira, Ph.D.

Professor, COLLEGE OF MEDICINE MOLECULAR MEDICINE
  • Our main research interest is defining the reaction and regulatory mechanisms of the first and terminal heme biosynthetic pathway enzymes, 5-aminolevulinate synthase (ALAS) and ferrochelatase (FC). Iron overload is a clinically important feature of sideroblastic anemia, X-linked SA, and myelodysplastic syndrome, which often results from either ineffective hematopoiesis or the repeated transfusions undergone by the patients to manage their erythropoietic defects. The pathological consequences of mitochondrial mishandling of iron and heme synthesis are also evident in erythropoietic porphyrias. There is no cure for the above disorders, and thus understanding the mechanisms of the terminal stages of erythropoiesis becomes necessary for discovering novel therapeutic targets. Towards this goal, our on-going research focuses on establishing 1) whether succinyl-CoA synthetase b-subunit allosterically fine-tunes the activity of erythroid ALAS and 2) the mechanism of Fe2+ delivery to FC.
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Ph.D. Students

  • The Ferreira laboratory focuses on the heme biosynthetic pathway, which consists of eight enzyme-catalyzed reactions. Heme biosynthesis occurs under the control of the enzyme 5-Aminolevulinate synthase (ALAS), which catalyzes the first and rate-limiting reaction of succinyl-CoA with glycine to produce 5-aminolevulinate (ALA), CoA, and CO2. Loss-of-function and gain-of-function mutations in human erythroid ALAS (ALAS2) have been associated with two diseases, x-linked sideroblastic anemia (XLSA) and x-linked dominant protoporphyria (XLDPP), respectively. In XLDPP, the gain-of-function of the ALAS2 enzyme causes extreme photosensitivity resulting from protoporphyrin IX accumulation in the skin of patients. Although the mutations associated with XLSA occur throughout the ALAS2 gene, those associated with XLDPP all correspond to modifications in the C-terminus of the mature enzyme. The 26 C-terminal amino acids of mature ALAS2 are highly conserved, and yet differ from those in ALAS1, the housekeeping ALAS isoform, suggesting that the C-terminus may play an important role in erythroid-specific regulation. The overall hypothesis of my project is that the C-terminal region of ALAS2 provides specific regulatory mechanisms of heme biosynthesis to precursor erythroid cells.
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Post Docs

  • My current research focuses on understanding the role of the Amyloid Precursor Protein (APP) in pancreatic cancer. It is well known that pancreatic cancer has a poor prognosis and very low 5-year survival rates. Early detection poses a challenge mainly owing to the location of this organ and a non-symptomatic progression. At the molecular level, the oncogene RAS is known to be mutated and overexpressed in this cancer and the signaling pathways are somewhat understood. Using several pancreatic cancer cells lines, our recent findings show that APP is overexpressed in most pancreatic cancer cells lines as well. Preliminary studies have shown that APP can regulate RAS transcription levels and knock down of APP can inhibit RAS protein expression. Using this information, my project aims to understand the mechanism of regulation of RAS by APP and to establish APP, its processed fragments, and associated signaling pathways as possible targets for drug development against pancreatic cancer.
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