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Title page for ETD etd-07152009-140729

Type of Document Dissertation
Author Carter, Melissa Diane
URN etd-07152009-140729
Title Hemozoin: A Paradigm for Biomineralization in Disease
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
David W. Wright Committee Chair
Craig W. Lindsley Committee Member
John A. McLean Committee Member
Richard N. Armstrong Committee Member
  • lipid peroxidation
  • HTS
  • HETE
  • HNE
  • beta-hematin
  • hemozoin
  • malaria
  • schistosomiasis
Date of Defense 2009-07-14
Availability unrestricted
Biomineralization is the formation of organic-inorganic composites by organisms. Originally evolved as a protective mechanism, this complex process has also become a recognized contributor to several disease states, ranging from kidney stone disease (nephrolithiasis) to parasitic diseases like malaria. The characteristic three-step process for the formation of biominerals is defined by the supramolecular preorganization of a nucleating template, the interfacial molecular recognition of crystal nuclei and the cellular processing of resultant aggregates. Hemozoin formed in the heme detoxification pathway used by the malarial parasite Plasmodium falciparum and schistosomal parasite Schistosoma mansoni represents a paradigm for pathogenic biominerals. Current research indicates that a supramolecular lipid template organizes heme previously released during hemoglobin catabolism. Nucleation and growth of the heme aggregate serves to protect the parasite from the toxic effects of free heme. Given the mechanisms of biomineralization, it is not surprising to discover that century-old antimalarial compounds function by disrupting key interactions between the heme substrate and template. Subsequently, the heme-aggregate is released into the host vasculature and deposits in patients’ brains, spleens and livers where it disrupts host innate immune response. The underlying basis of this immunomodulating activity appears to result from hemozoin mediated lipid peroxidation. Understanding the relationships between hemozoin formation and its pathogenic activity with the host immune response represents a significant challenge to chemical biology. The body of work presented herein provides an analysis of hemozoin mediated lipid peroxidation in a Schistosoma mansoni infected murine model as well as the development of a novel in vitro hemozoin crystallization assay for the high throughput screening of potential antimalarial lead compounds.
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