The National Institutes of Health has awarded BloodCenter of Wisconsin $13.2 million for the continuation of its Program Project Grant (PPG) entitled “Molecular & Cellular Mechanisms in Transfusion Medicine.” The overall scientific synergy of ideas, reagents and expertise afforded by the multiple collaborations proposed should enable this Program Project in Transfusion Medicine Research to advance our understanding of the biology of blood and vascular cells, and to apply findings made toward treating blood diseases and enhancing the effectiveness of modern-day transfusion therapy.
Dr. Peter J. Newman, Vice President of Research and Associate Director of the BRI, is Principal Investigator for this multi-project grant. The latest award provides an additional five years of funding (years 21-25) for the PPG’s five projects and three cores.
Listed below are the projects that make up the PPG.
Project 1, “Molecular Mechanisms of Platelet Activation and Adhesion” – Peter J. Newman, Ph.D. Studies aim to further our understanding of the cell surface receptors and associated signaling pathways that regulate platelet activation and adhesion.
Project 2, “Protein C Pathway Function in Hematopoiesis” – Hartmut Weiler, Ph.D. This study investigates a novel interaction between the blood coagulation mechanism and the function of the hematopoietic system that is mediated by the natural protein C pathway.
Project 3, “B Cell Responses in Heparin-Induced Thrombocytopenia” – Demin Wang, Ph.D. This study aims to understand the cause of heparin-induced thrombocytopenia, one of the most common drug-induced life-threatening blood diseases.
Project 4, “Adhesion Receptor Signaling in Platelets” – Debra K. Newman, Ph.D. The objective of this study is to understand the mechanisms underlying platelet activation.
Project 5, “Critical Molecular Interactions of VWF and FVIII” – Robert R. Montgomery, M.D. This project addresses a novel strategy to carry out gene therapy of hemophilia, a severe clinical bleeding disorder.
In addition to the PPG, Dr. Newman has renewed funding from the National Heart, Lung, and Blood Institute for continuation of his research project grant, "Molecular Biology and Function of PECAM-1." PECAM-1 is expressed on the surface of circulating platelets, monocytes, neutrophils, and selected T-cell subsets and is also a major constituent of the endothelial cell intercellular junction. The goal of this proposal is to improve understanding of the function of PECAM-1 in the blood and vascular cells in which it is expressed. Information derived from this investigation will lead to improved understanding of the molecules and events that regulate inflammation, thrombosis, and the immune response.
Peter J. Newman, Ph.D.
VP for Research
Blood Research Institute
BloodCenter Investigator Awarded R01 Grant to Address Problem of Donor Iron Deficiency
Dr. Alan Mast has received four years of funding from the National Heart, Lung, and Blood Institute for studies that will provide important information on the efficacy of various approaches for iron replacement in blood donors and lay the groundwork for effective programs that can be readily implemented by community blood centers. “Caring for Those Who Share: Mitigating Iron Deficiency in Regular Blood Donors” will utilize a consortium of three blood centers to assess potential interventions that will prevent/mitigate iron deficiency in blood donors. This will contribute to improved public health by preventing the adverse consequences of iron deficiency in blood donors such as fatigue and decreased exercise tolerance, as well as neurological symptoms such as decreased cognitive function, pica and restless leg syndrome.
Dr. Mast also has renewed funding from the National Heart, Lung, and Blood Institute for his research project grant, "Association of tissue factor pathway inhibitor with endothelium." Tissue factor pathway inhibitor (TFPI) is an endothelial associated anticoagulant protein that prevents the formation of blood clots.Dr. Mast's laboratory will investigate cellular responses to injury and inflammation, balancing the development of blood clots necessary to prevent severe bleeding while at the same time avoiding the development of intravascular blood clots that can result in heart attack or stroke and enhance tumor metastasis.The long-term goal of this study is to develop methods for prevention and treatment of the adverse effects of intravascular TF activity based upon understanding its pathobiology through studies of its inhibition by TFPI.
Alan E. Mast, M.D., Ph.D.
Investigator
Blood Research Institute
NIH Funds Grant to Study HNA-3a and -3b Antibodies and Antigens
The NIH has awarded Dr. Richard Aster a two-year exploratory/developmental research grant, “Prevalence and immunogenicity of HNA-3a and -3b antibodies and antigens.” Transfusion-associated acute lung injury (TRALI) is a serious complication of blood transfusion and the most common cause of transfusion-related mortality. Transfusion of antibodies specific for white blood cells (leukocytes) is a major cause of TRALI. Antibodies against a leukocyte antigen, designated HNA-3a, are especially prone to cause severe, often fatal TRALI but, for technical reasons, it has not been possible to test blood donors to detect them. The goal of this study is to overcome this obstacle.
Dr.Aster also has NIH funding for his longstanding research project grant, "Hemorrhagic Diseases." This grant aims to determine and characterize molecular roles and properties associated with alloimmune blood disorders and drug-induced immune thrombocytopenia. This grant also proposes to address important unresolved questions concerning performance of diagnostic testing and interpretation of test results to improve diagnosis and management of heparin-induced thrombocytopenia.
Immune-mediated blood disorders and other types of drug sensitivity are a major cause of morbidity and mortality. The proposed studies will lead to a better understanding of causation and improved diagnosis and treatment.
Richard H. Aster, M.D.
Senior Investigator
Blood Research Institute
NIH Grant to Study Rap1b Function Issued Under ARRA
Gilbert C. White, II, M.D. Executive VP for Research
Blood Research Institute
Dr. Gilbert C. White, II, has been awarded a two-year research project grant (R01) issued under the American Recovery and Reinvestment Act of 2009 (ARRA) by the National Heart, Lung, and Blood Institute. The purpose of the work in this proposal is to explore the membrane interactions of rap1b in more detail in order to better understand its mechanism of action. Rap1b is a ubiquitous, membrane associated low molecular weight GTPase that has been shown to be important for integrin-mediated platelet aggregation and adhesion.
The overall goal of this application is to understand how platelets respond to an injury to a blood vessel, as well as the mechanisms involved with their response. These findings will provide insight into how the body heals bleeding injuries, as well as the underlying cause of blood clotting conditions.
BloodCenter Investigator Awarded R21 Grant Under the Recovery Act
Bonnie Dittel, Ph.D. Investigator Blood Research Institute
The NIH has awarded Bonnie Dittel, Ph.D., a two-year exploratory/developmental research grant issued under the American Recovery and Reinvestment Act of 2009, "Identification of a protein that elicits immune-mediated neuronal dysfunction." Many diseases of the nervous system, including multiple sclerosis (MS), are often associated with damage to neurons resulting in disability. The goal of this proposal is to purify and identify the protein responsible for the neuronal damage such that it can be investigated as a new therapeutic target for the treatment of neurodegenerative diseases in subsequent studies.
Dr. Dittel has also obtained NIH funding for her grant, “Role of B Cells in Regulating Autoimmunity.” In the central nervous system (CNS) of MS patients, the immune system facilitates the development of inflammatory lesions that result in permanent tissue damage resulting in disability if not resolved. B cells have been shown to regulate this autoimmune inflammation in the animal model of MS. This project investigates the cellular mechanisms utilized by regulatory B cells in the resolution of CNS inflammation, resulting in recovery from disease. Since little is known about how B cells regulate inflammation, these studies can potentially contribute to the development of therapies for a variety of human inflammatory disease in addition to MS.
NIH Grant to Study Platelet Activation
Debra K. Newman, Ph.D. Investigator Blood Research Institute
Dr. Debra Newman has received an NIH grant to study "Negative Regulation of Platelet Activity." The goal of this grant is to develop a more complete list of inhibitory molecules in platelets, to thoroughly characterize the signaling pathways in which these molecules function, and to improve our understanding of how these molecules and pathways interact to ultimately influence the platelet activation state.
The information derived from these studies can contribute to improved diagnosis and treatment of bleeding disorders, myocardial infarction and stroke.
NIH Funds BloodCenter Studies on Activated Protein C
Hartmut Weiler, Ph.D. Investigator Blood Research Institute
The National Institutes of Health has awarded Dr. Hartmut Weiler a grant to study the effectiveness of “Activated Protein C for Treatment of Radiation Combined Injury.” APC has already been shown to reduce sepsis mortality in animal models and human patients, and it is approved for clinical use in the treatment of severe sepsis. Dr. Weiler’s evaluate the use of recombinant forms of the endogenous activated protein C (APC) molecule for the therapeutic prevention of bone marrow failure, infection, and ultimately mortality as they may occur after incidental whole body exposure to nuclear radiation. Outcomes of the study are expected to validate APC as a safe and effective treatment for victims of nuclear accidents and other threats involving radiation exposure.
Dr. Weiler has also received an NIH grant to study the "Mechanism of Activated Protein C Action in Sepsis Therapy." Recombinant activated protein C (APC) is the only available sepsis drug shown to reduce absolute mortality of patients with severe sepsis, but it has serious side effects and is not effective for all patients. This study will investigate whether novel APC variants that promote survival but lack the harmful side effects of normal APC can significantly improve the efficacy of APC therapy.
$2 million Grant to Study Immunologic Role of Signaling Molecules
Demin Wang, Ph.D. Investigator Blood Research Institute
Demin Wang, Ph.D. has been awarded a grant from the National Institutes of Health to study “PLCgs in B Cell Biology and Autoimmunity.” This award from the National Institute of Allergy and Infectious Diseases provides $2,000,000 over 5 years.
This project seeks to understand the roles of two important signaling molecules, PLCg1 and PLCg2, in the development of lymphocytes, including the removal of autoreactive B cells and the molecular mechanism by which PLCgs regulate these processes. The study may provide new clues to the molecular pathogenesis of autoimmune and immunodeficiency diseases, and help identify novel targets for specific therapies.
NIH Grant to Study Natural Killer Cell Activation
The National Institutes of Health has awarded Subramaniam Malarkannan, Ph.D. a grant to study “Molecular Mechanisms of Natural Killer Cell Activation.” This grant from the National Institute of Allergy and Infectious Diseases provides $1,726,845 over 5 years for Dr. Malarkannan’s studies.
Natural killer (NK) cells are an important component of the immune system because of their ability to recognize and destroy tumor and infected cells. They do this by scanning for the normal expression levels of MHC class I molecules and activating ligands on target cells. Dr. Malarkannan’s Laboratory will examine the interplay between two receptor signaling pathways, one that activates NK cell function and one that inhibits it. His laboratory will also define intricate signaling events that occur inside the NK cells after its activation.
Understanding how receptor signals impact NK cell function will lead to the development of cellular immunotherapies for the treatment of hematological malignancies.
Subramaniam Malarkannan, Ph.D. Investigator Blood Research Institute
BloodCenter Scientists to Study How to Improve Vaccines
BloodCenter of Wisconsin’s Blood Research Institute (BRI) has received a $14 million contract from the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases to study how the body develops immunity to the flu in children, the elderly and those with compromised immune systems. Jack Gorski, Ph.D., Senior Investigator and molecular immunologist for BloodCenter of Wisconsin, is the study’s Principal Investigator.
The primary goal of the study is to gain an understanding of how to improve vaccine responses. “Researchers are particularly interested in how T-cells, the white blood cells that fight off infections, function in the face of the influenza virus and vaccine,” said Gorski.
This new contract is related to a $12 million five-year grant awarded in 2004, which will give scientists more insight into why some people exposed to the illness get sick and some do not. The ultimate goal of the study is to help determine how the immune system deals with new and related viruses in an effort to provide basic information about population immunity for the government’s bio-defense program.
BloodCenter is the lead center for this contract. Other participants in the study include Medical College of Wisconsin, University of Utah, Tufts University and University of Massachusetts Medical School.
Jack Gorski, Ph.D. Sr. Investigator Blood Research Institute
$1.8 million Award to Study Sickle Cell Disease
Cheryl Hillery, M.D., was recently awarded a 5-year grant by the National Institutes of Health to study “Mechanisms of Vaso-occlusion in Sickle Cell Disease.”
The major cause of death among patients with sickle cell disease (SCD) is progressive organ damage caused by the inability of sickle red blood cells to deliver oxygen to tissues. It is thought that increased inflammation and increased activity of the coagulation system caused by SCD contributes to a complete stoppage of blood flow, increasing the likelihood of tissue death.
These studies will clarify the interrelated roles of the coagulation system, vascular injury and
inflammation in the evolution of sickle cell-induced vascular disease. They will also provide insights into the value of targeted anticoagulant/anti-inflammatory therapies for the treatment and prevention of SCD vascular disease.
Cheryl Hillery, M.D. Investigator Blood Research Institute
$4.5 million Program Project Grant Focuses on Bleeding Disorder
Dr. Robert R. Montgomery is the Principal Investigator for the recently awarded NIH Program Project Grant (PPG), “Molecular and Clinical Biology of VWD.” Studies are aimed at developing scientific and clinical understanding of the bleeding disorder von Willebrand Disease (VWD).
Dr. Montgomery’s PPG involves projects located at the Blood Research Institute, Medical College of Wisconsin, and Queen’s University in Canada. An integral part of the project involves VWD patient samples sent to BloodCenter of Wisconsin’s Hemostasis Lab for testing. Samples will come from treatment centers in Atlanta, Detroit, Iowa City, Indianapolis, Houston, New Orleans, and Pittsburgh. BloodCenter of Wisconsin's Comprehensive Center for Bleeding Disorders (CCBD) will serve as the primary collection center.
A Program Project Grant is a funding mechanism that supports a group of investigators with different areas of expertise, forming what NIH calls a “synergistic research program designed to achieve results not attainable by investigators working independently.”
Robert R. Montgomery, M.D. Sr. Investigator Blood Research Institute
