Defining the novel eukaryotic biology of the Apicomplexan plastid

Summary

Principal Investigator: Ellen Yeh
Abstract: DESCRIPTION (provided by investigator): Apicomplexan parasites contain an essential plastid organelle called the apicoplast. Given its unique features, the apicoplast is a source of novel eukaryotic biology in these parasites and a potential Achilles'heel for drug and vaccine development. The challenge in taking advantage of the apicoplast's unique biology for therapeutic development has been to identify the specific pathways and functions that can be targeted. My overall goal is to elucidate the novel pathways and functions of the apicoplast in two important human pathogens: Plasmodium spp parasites, a leading global infectious disease killer, and Babesia spp parasites, an emerging human infection that threatens the transfusion blood supply. In an important step towards this goal, I recently demonstrated that the sole essential function of the apicoplast in blood-stage P. falciparum is the biosynthesis of isoprenoid precursor, IPP. As such, P. falciparum parasites that have completely lost their apicoplast can be rescued by supplementation with IPP. Significantly, chemical rescue of "apicoplast(-)" parasites enables new approaches and novel experiments as outlined in this application. I investigate several novel aspects of apicoplast biology: 1) identification of protein factors required for a critical and unique step during protein import into the apicoplast, 2) identificatio of the small molecule isoprenoids derived from IPP that likely have essential cellular functions in P. falciparum, and 3) determination of the function of the apicoplast in Babesia parasites, which share important pathogenic and evolutionary features with P. falciparum. The scope of these aims allows a thorough investigation of the novel features of the Apicoplexan apicoplast that will yield fascinating eukaryotic biology and promising therapeutic targets. PUBLIC HEALTH RELEVANCE: Apicomplexan parasites which include Plasmodium falciparum, cause of the most deadly form of human malaria, and Babesia spp parasites, an emerging threat to the transfusion blood supply, contain a unique plastid organelle that is a potential Achilles'heel for drug development. In this application, I propose to better understand the novel biology of the organelle and its role in the pathogenesis. This work has direct and significant implications for development of novel therapeutics against these important human pathogens.
Funding Period: 2012-09-14 - 2017-08-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Targeting a Unique Enzyme Mechanism in Non-Mammalian Isoprenoid Biosynthesis
    Jessica M Smith; Fiscal Year: 2013
    ..The rationale for the proposed studies is that developing strategies for selective inhibition of this enzyme will provide new tools for investigating this essential pathway in pathogens and will lead to new anti-infective agents. ..
  2. Molecular Targets Phase III CoBRE
    Donald M Miller; Fiscal Year: 2013
    ..The robust translational research infrastructure at the James Graham Brown Cancer Center and University of Louisville will ensure the success and sustainability of this unique program. ..
  3. Prenyl Synthase Inhibitors: Novel Anti-Infective Agents
    Eric Oldfield; Fiscal Year: 2013
    ..Focus will be on developing inhibitors for three unique targets in malaria parasites, and on the use of novel drugs against sleeping sickness. ..
  4. Systems Biology of Plasmodium falciparum: Building and Exploring Network Models
    Yufeng Wang; Fiscal Year: 2013
    ..Such networks are the cornerstones of a systems-level view of pathogen biology, a view that will allow us to transform disparate types of data into biological insights for drug development. ..
  5. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  6. Malaria Phosphatase Inhibitors Identified as a Potential New Malaria Treatment
    Wei Zheng; Fiscal Year: 2013
    ..falciparum phosphatase will be used in conjunction with high throughput screening assays. These studies will be important for developing chemo prophylaxis directed against a brand new target in a major human pathogen. ..
  7. Deciphering apicoplast function during blood stage Plasmodium infection
    Ellen Yeh; Fiscal Year: 2013
    ..The proposed research and career development activities will be critical in the preparation for an academic career and provide ample opportunities for a future in independent research. ..
  8. Genetic dissection of parasite metabolism
    Boris Striepen; Fiscal Year: 2013
    ..The studies will provide important information to guide the development of drug treatments and will lead to a detailed understanding of host-parasite interaction at the metabolic level. ..
  9. Biology of the Apicomplexan Plastid
    Boris Striepen; Fiscal Year: 2013
    ..A detailed understanding of the biology of this structure will lead us to new parasite specific interventions to treat and prevent disease. ..
  10. Attenuated malaria sporozoite vaccine using a P. falciparum blood-stage auxotroph
    STEPHEN LEV HOFFMAN; Fiscal Year: 2013
    ..These studies will establish a vaccine candidate with optimal immunogenicity and a critical safety feature of being unable to sustain replication in erythrocytes if any parasites break through from the liver. ..
  11. Membrane Permeable Diphosphate Analogs Targeting Pathogen Isoprenoid Biosynthesis
    CAREN L MEYERS; Fiscal Year: 2013
    ..These studies will provide a foundation for the transformation of highly polar, potent inhibitors of isoprenoid biosynthesis into useful therapeutic agents for the treatment of infectious diseases. ..
  12. FOSMIDOMYCIN RESISTANCE IN PLASMODIUM FALCIPARUM
    AUDREY RAGAN ODOM; Fiscal Year: 2013
    ..falciparum genome, and identify new targets for much-needed antimalarial drug development. ..
  13. Unique functions of the mitochondrial tRNA import machinety in T. gondii
    Lilach Sheiner; Fiscal Year: 2013
    ..gondii mitochondrion and hence contribute to the design of new countermeasures, also of relevance to other apicomplexan parasites such as the causative agent of malaria, Plasmodium falciparum. ..
  14. Comparative Biology of Tissue Repair, Regeneration and Aging
    Kevin Strange; Fiscal Year: 2013
    ..The proposed COBRE will greatly enhance MDIBL's growth and development, which in turn will contribute to the continued growth and enhancement of the biomedical research infrastructure in Maine. ..
  15. Babesiosis: An Emerging Infectious Threat to Transfusion Medicine
    Cheryl Ann Lobo; Fiscal Year: 2013
    ..Recognizing that Babesia is an expanding blood safety threat we are interested in the development of viable interventions to detect and halt transmission of these pathogens via blood transfusions. ..
  16. The role of the DOC2.1 protein in Toxoplasma gondii Ca2+- dependent exocytosis
    Marc Jan Gubbels; Fiscal Year: 2013
    ..Putative TgDOC2.1 interaction partners identified by either method will be validated by co-localization studies in the parasite. Altogether, we will define the mechanism behind the conserved microneme secretion process. ..
  17. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  18. Mitochondrial Functions in Malaria Parasites
    Akhil B Vaidya; Fiscal Year: 2013
    ..These studies have the potential to be highly valuable in developing strategies for chemotherapeutic intervention affecting validated targets of malaria parasites. ..
  19. Secretion, protein targeting, and lipid metabolism in African Trypanosomes
    James D Bangs; Fiscal Year: 2013
    ..These studies will broaden our knowledge of basic cell biological processes in all eukaryotes, and will lay the groundwork for targeting the sphingolipid pathway for novel drug development. ..
  20. Conditional probes of secretory protein function in malaria parasites
    SEAN TAYLOR PRIGGE; Fiscal Year: 2013
    ..Successful development of a conditional localization tool will enhance our ability to probe the basic biology of malaria parasites and will allow us to validate potential targets for therapeutic intervention. ..