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Title page for ETD etd-04072009-104423


Type of Document Dissertation
Author Rutledge, Alexandra Catherine
URN etd-04072009-104423
Title The role of fatty acid oxidation in disruption of macrophage function
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
David W. Wright Committee Chair
Brian Bachmann Committee Member
Daniel Liebler Committee Member
David Cliffel Committee Member
Keywords
  • malaria
  • beta-hematin
  • hemozoin
  • lipid peroxidation
Date of Defense 2009-04-01
Availability unrestricted
Abstract
Hemozoin (Hz), the heme detoxification biomineral formed during the intraerythrocytic stage of malaria, has long been suspected of contributing to immunomodulations that occur during P. falciparum infection. Rupture of parasitized red blood cells releases cellular debris, including Hz, into the hostís vasculature and triggers an innate immune response. The typical response of phagocytic cells to such foreign material includes oxidative burst and degradation. However, phagocytosis of Hz impairs these innate functions. It has been suggested that Hzís immunological activity may not stem from the heme moiety, but rather from lipid peroxidation products that are present on its surface and introduced into the cell during phagocytosis. In its native state, Hz is coated by an array of proteins, nucleic acids, and lipid peroxidation products including a racemic mixture of 5-, 8-, 9-, 11-, 12-, and 15-hydroxyeicosatetraenoic acids (HETEs) and 9- and 13- hydroxyoctadecadienoic acids (HODEs). Elevated levels of 4-hydroxynonenal (HNE) have also been detected in hemozoin-laden monocytes at the highest reported concentration of any biological system to date. The goal of this dissertation is to investigate the role of fatty acid oxidation in the disruption of macrophage function. Specifically, the ability of the biologically naÔve synthetic analogue of hemozoin (β-hematin [BH]) to mediate the oxidation of arachidonic acid to HNE, HETEs, and isoketals is discussed in Chapter II. Given the immunomodulatory activity of HNE and 15-HETE, Chapter III examines the cellular responses to individual components of Hz (BH, HNE, and 15-HETE) in the context of malaria infection using global microarray technology. The ability of HNE to modulate MMP9 regulation and NF-κB signaling was suggested by a number of differentially expressed transcripts and correlates with documented malaria pathophysiology. Thus, Chapter IV discusses the ability of HNE to disrupt the programmed functions of a triggered immune response and examines the specific mechanisms leading to altered matrix metalloproteinase (MMP) 9 and inducible nitric oxide synthase (iNOS) expression.
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