Integrated signaling of eicosanoids in HSC formation and regeneration


Principal Investigator: Trista E North
Abstract: DESCRIPTION (provided by applicant): Disorders of the hematopoietic system are a common cause of morbidity and mortality in the United States. In vertebrates, definitive hematopoietic stem cells (HSCs) produce each of the mature blood cell lineages of an individual throughout its lifetime. Defects in HSC formation or differentiation can lead to devastating diseases in childhood or to leukemia. The first HSCs arise in the embryo from an area encompassing the dorsal aorta, termed the aorta-gonad mesonephros (AGM) region. Most genes involved in HSC formation are highly conserved across vertebrates, and continue to regulate HSC self-renewal and differentiation in the adult. The transcription factor Runx1, a frequent target of chromosomal mutation in human leukemia, is absolutely required for HSC specification in mammals;runx1 expression is conserved in zebrafish, appearing robustly by 36 hours post fertilization (hpf) in the AGM. Through a zebrafish chemical screen for modifiers of runx1 expression, we have found that compounds related to eicosanoid production and signaling modulate HSC number. The eicosanoid prostaglandin E2 (PGE2) can regulate embryonic HSC formation and adult homeostasis across vertebrate species. In contrast, the function of related eicosanoids, cannabinoids (CB), in HSC development and PGE2-mediated repair has not been addressed. Our long-term goal is to understand the molecular and cellular mechanisms by which various factors interact to affect hematopoiesis. Our objective here is to characterize the functional implications of eicosanoid cross-regulation on HSC formation, proliferation and migration during development and recovery after injury, in both zebrafish and mice. Our central hypothesis is that two related eicosanoid subclasses, PGE2 and CBs, act individually and in concert to exert specific effects on HSCs during embryogenesis and regeneration. This hypothesis has been derived from our own screening results and subsequent preliminary data as well as previously published studies. The rationale for our work is that a detailed understanding of the impact of CB ligands on PGE2-mediated HSC growth and proliferation will enable targeted therapeutic approaches for the treatment of bone marrow failure states, recovery from chemotherapy, or after HSC transplant. In Specfic Aim 1, we plan to investigate the effects of CB agonists/antagonists on HSC specification and proliferation during hematopoietic development in zebrafish. We will examine the conservation of this activity during and after marrow injury. In Specific Aim 2, we plan to analyze the combined effects of CB agonists and PGE2 on HSCs. We postulate that PGE2 and CB-agonists together can increase HSC number in the AGM to a higher level than each of these compounds alone. We will then examine if the interaction between eicosanoids is relevant in directing enhanced marrow recovery after injury in zebrafish and murine transplantation models and in assays with human cord blood. These results are expected to reveal deeper insight into interactive roles of inflammatory mediators in marrow regeneration and have relevance for combinatorial targeting to direct clinical outcome in transfusion biology.
Funding Period: 2012-08-07 - 2014-07-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Characterization of regulators of hemotopoietic stem cell homeostasis
    Trista E North; Fiscal Year: 2013
    ..This work has great relevance for the development of novel agents to regulate leukemia, and for recovery from chemotherapy and bone marrow transplant...
  2. Defining Estrogenic Regulation of Hematopoietic Stem Cell Formation and Function
    Trista E North; Fiscal Year: 2013
    ..Using murine assays, they will examine how these compounds effect HSC function across vertebrate species. ..
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  4. Infections and The Stability of Transplantation Tolerance
    Anita S Chong; Fiscal Year: 2013
    ..abstract_text> ..
    LEONARD IRA ZON; Fiscal Year: 2013
  6. Mitochondrial Target for Radiation Mitigation
    Joel S Greenberger; Fiscal Year: 2013
    ..abstract_text> ..
  7. Mechanisms mediating hematopoietic stem and progenitor cell trafficking
    Paul S Frenette; Fiscal Year: 2013
    ..Here, we will explore further the hypothesis that the retention of hematopoietic stem and progenitor cells in the niche is regulated by differing signals from the sympathetic nervous system and macrophages. ..
  8. Eliciting B cells to produce anti-HIV gp41 MPER-specific neutralizing antibodies
    Ellis L Reinherz; Fiscal Year: 2013
    ..In conjunction with Projects 1- 3, kinetics of memory B cell and long-lived plasma cell populations will be ascertained and optimized. An Administrative Core with a Partnership Plan is included. ..
  9. Mechanisms of State Switching in Sleep and Sleep Apnea
    Clifford B Saper; Fiscal Year: 2013
    ..This work will help to design interventions for improving the health of patients with OSA. ..
  10. Role of the zinc finger transcription factor ZBP89 in blood &vascular developmen
    M Amin Arnaout; Fiscal Year: 2013
    ..We have discovered a transcription factor that lies at the cross road of blood and blood vessel development. We are proposing a series of studies to pinpoint the role of this factor, and define the developmental networks it coordinates. ..
  11. Arterial Dysfunction: Basic and Clinical Mechanisms
    Thomas Michel; Fiscal Year: 2013
    ..Gladyshev. P. Libby directs the Redox Biomarkers Core;metabolic characterizations of mouse models studied in this Program will take place at the Yale Mouse Metabolic Phenotyping Center, led by G. Shulman. ..
  12. Identification of biomechanical pathways that promote hematopoiesis
    PAMELA LYNN WENZEL; Fiscal Year: 2013
  13. HSC Diversity: Regulation by Clonal Selection vs Epigenetic Induction
    Irving L Weissman; Fiscal Year: 2013
  14. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  15. Hyaluronan Matrices in Vascular Pathologies
    Vincent C Hascall; Fiscal Year: 2013
    ..abstract_text> ..
  16. Martin Delaney Collaboratory to Eradicate HIV-1 Infection
    David M Margolis; Fiscal Year: 2013
    ..We are convinced that together we will catalyze advances that will ultimately lead to the eradication of HIV infection. ..
  17. Identifying the molecular basis for hormonal influence on hematopoiesis
    Aparna Vasanthakumar; Fiscal Year: 2013
  18. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
    ..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..