The endogenous cannabinoid ligands, termed endocannabinoids have emerged as important lipid mediators that regulate central and peripheral neural functions as well as immune responses. The exogenous and endogenous cannabinoid ligands bind to cannabinoid receptors: the predominant central cannabinoid receptor type 1 (CB1) and the peripheral cannabinoid receptor type 2 (CB2). CB1 and CB2 are members of the G-protein coupled receptor family. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are main endocannabinoids: While 2-AG is preferentially degraded by monoacylglycerol lipase (MGL), AEA is hydrolyzed primarily by fatty-acid amide hydrolase (FAAH). The potential role of endogenous and exogenous ligands as well as cannabinoid receptors, CB1 and CB2, in the regulation of hematopoiesis and HSPC trafficking and mobilization is not known.

Based on our preliminary results, we hypothesize that the endocannabinoid system is a physiological regulator of hematopoiesis and that endocannabinoids are involved in HSPC mobilization, which can be used for clinical conditions such as bone marrow transplantation. In this study, we aim to analyze hematopoietic stem and progenitor cell mobilization and long term reconstitution of the hematopoietic system by anandamide using specific inhibitors for enzymes fatty acid amide hydrolase (FAAH). These studies should provide insights into novel pathways involved in the mobilization and trafficking of HSPC and assist in the development of new treatment interventions in HSC transplantation.

Rose Beck, MD, PhD Assistant Professor, Principal Investigator, Case Western Reserve, University School of Medicine-Department of Pathology

Notch-induced NK Cells for Cell Therapy in Hematologic Maligancy

Natural killer (NK) cells are cells of the immune system, which are able to directly kill tumor cells.  Our lab has used signaling through Notch, a molecule critical for cell-fate decisions, to expand human NK cells from hematopoietic precursor cells found in umbilical cord blood.  The phenotype and functionality of these Notch-induced NK cells suggest that these cells might be useful as cell therapy in the setting of hematologic malignancy, such as leukemia.  The project funded by the National Blood Foundation will examine the clinical potential of Notch-induced NK cells by looking at their ability to kill hematopoietic tumor cells in culture and in animal models.

Christine M. Cserti-Gazdewich, MD, FRCP, Assistant Professor, University of Toronto, Toronto General Hospital, University Health Network.

Cytoadherence in Pediatric Malaria (CPM) Study.

Every year, nearly 2 million children die from infection with Plasmodium falciparum malaria.   In Africa, most blood transfusions given to children are for treatment of malaria.  When red blood cells (RBC) become infected with malaria, a parasite-derived knob protein, termed PfEMP-1, erupts on the RBC surfaces.  PfEMP-1 adheres to several blood group molecules, including those found on other RBC, on blood vessels, and on the cells that normally help to stop bleeding (platelets). The multi-cellular adhesion results in a dangerous interruption in blood flow and reduces oxygen delivery to vital organs, causing brain injury (cerebral malaria), systemic shock (lactic acidosis), and death. Depending on an individual's inherited blood groups of relevance, adhesion may be extensive or limited.   In the laboratory, PfEMP-1 adheres to RBCs via the A or B (but not the O) antigens of the ABO blood group system, and to platelets and blood vessels via platelet glycoprotein IV (CD36) and ICAM-1. Consistent with the expected evolutionary advantage of being deficient in these binding targets, blood type O and low-expression of CD36 are found more frequently among Africans.  The "Cytoadherence in Pediatric Malaria" (CPM) project is determining the distribution of adhesive blood group molecules in a cohort of 2000 Ugandan children according to the extent of malaria severity and death, and thus their ultimate clinical and evolutionary significance in malarial survival.  This knowledge may serve as the grounds for developing targeted cytoadhesion-interruption therapies in our fight against malaria.

Nobuharu Fujii, MD PhD, Principal Investigator, Fred Hutchinson Cancer Research Center,

Identification of Novel H-Y Antigens using Artificial Neural Network

The human Y chromosome encodes male-specific histocompatibility (H-Y) antigens that are recognized by female immune cells.  Immune responses against H-Y antigens can lead to sensitization of females against cellular blood products derived from males. Immune responses against H-Y antigens can also profoundly influence the outcome of sex-mismatched allogeneic hematopoietic cell transplantation by contributing to graft rejection, graft-versus-host disease (GVHD), or graft-versus-leukemia (GVL) activity.  The purpose of this study is to characterize the spectrum of H-Y antigens that can stimulate immune responses from a type of female immune cell called a CD8⁺ T lymphocyte.  The ultimate goal is to development strategies for selectively manipulating GVHD and GVL by engineering the immune response against H-Y antigens.

Mark R. Looney, M.D., Assistant Professor of Medicine, University of California, San Francisco, (UCSF), The Role of Platelets in Experimental Transfusion-related Acute Lung Injury (TRALI)

Dr. Looney is studying the mechanisms by which blood transfusions cause lung damage, a syndrome referred to as transfusion-related acute lung injury (TRALI).  TRALI is an important cause of morbidity and mortality from transfusion therapy.  Dr. Looney has developed a MHC I antibody-based mouse model of TRALI and is interested in how neutrophils and platelets interact causing the lungs to become leaky to plasma and proteins.  His research is examining molecular targets that may inhibit platelet-neutrophil interactions in experimental TRALI, which may have important implications for patients who develop lung injury from blood product transfusions.

Adam Munday, MD PhD, Research Scientist, Puget Sound Blood Center,

Platelet Cold Receptors: Potential for Improving Platelet for Improving Cold Storage

Every day, thousands of platelet units are transfused in the United States to prevent bleeding in patients with low platelet counts or to treat those who are actively bleeding.  Platelets are a precious commodity that must be replenished on a daily basis by blood donation because at the present time they can only be stored for 5 days before they must be discarded.  The reason for this is that they cannot be refrigerated, thereby greatly increasing the likelihood that bacteria that were present when the blood was drawn can multiply to the point that they will cause serious illness or death in anyone transfused with the platelets.  The reason the platelets cannot be refrigerated is that when they are subsequently transfused into patients, they are cleared very rapidly from the blood and therefore protect the patient from bleeding for only a very short time compared to platelets that are stored at room temperature.  The reasons for this rapid clearance are not well understood.  Dr. Munday will try to uncover the mechanisms of the rapid clearance of cold stored platelets which may lead to methods that will allow platelets to be refrigerated while maintaining their viability after transfusion.  This development will greatly lessen the wastage rate of the platelets and produce a cost savings for blood banks, hospitals, and patients.

Beth Shaz, MD Assistant Professor in Pathology at the Emory Center for Transfusion and Cellular Therapies, Emory University School of Medicine,

Blood Donation considerations in African Americans

Dr. Shaz proposes to study blood donation factors in African Americans through determining regional blood donation rates and donor deferral rates based on race, estimating African American national donor eligibility rates, and surveying individuals to identify racial differences in motivators and barriers to blood donation.  These data will contribute to the understanding of the racial differences in the blood donation process and the subsequent establishment of interventional strategies to increase African American blood donation.

2008 NBF Grant Recipients Press Release

1985 - 2007 Scientific Research Grant Recipients/Scholars