P01HL167668

Molecular mechanisms of immune thrombocytopenia in transfusion medicine - overall component – project summary/abstract.

This revised application for a program project seeks support for a coordinated, multi-disciplinary investigation of molecular mechanisms that underly clinically important immune-mediated thrombocytopenic and thrombotic disorders.

The program is housed at Versiti's Blood Research Institute and Children's Hospital of Philadelphia – both nationally renowned facilities with long-standing commitments to basic, translational, and clinical blood-related research, particularly in the areas of platelet immunology, platelet activation, thrombosis, and B cell immunobiology.

These disciplines are of programmatic significance to the NHLBI, and of central importance to transfusion medicine and classical hematology - disciplines that, despite their impact on the nation's health, are currently underrepresented in both human and financial resources.

Our application reflects ongoing, close collaborative ties amongst the project leaders, some for more than three decades, and is bolstered by a strong history of interdependence that has allowed us to tackle thematically related issues of clinical relevance and importance.

The central unifying theme of our application is to build on and develop a deeper understanding of clinically relevant immunological insults that lead to thrombocytopenia and downstream pathophysiological sequelae in the fetus, newborn, and adult.

The program comprises three highly synergistic, interdependent projects, each of which is characterized by (1) examination of an unpredictable pathology attributable to a subset of antigen-specific antibodies that, in addition to causing thrombocytopenia, also adversely affect other cell types, and (2) judicious use of preclinical mouse models that are specifically designed to investigate the etiology of different forms of immune thrombocytopenia.

Project 1: The immunobiology of fetal/neonatal alloimmune thrombocytopenia (FNAIT) employs a novel antigen-specific mouse model and a battery of clinically relevant monoclonal antibodies to define the functional significance of specific maternal antibody subpopulations that contribute mechanistically to, and may be diagnostic of, the severity of FNAIT.

The etiology of this disorder is examined by exploring routes of antigen exposure that cause maternal alloimmunization to occur unpredictably in first pregnancies.

Project 2: The immunobiology of heparin-induced thrombocytopenia (HIT) uses sophisticated human antibody cloning techniques and analysis to identify and characterize the specific pathogenic antibody subpopulations that cause HIT, and explores an intriguing role for the gut microbiome in the etiology of this man-made immunological disorder.

Project 3: The immunobiology of vaccine-induced thrombotic thrombocytopenia (VITT) examines novel mechanisms by which platelet factor 4, platelet basic protein, and neutrophil activating peptide 2 contribute to the etiology of this rare, but life-threatening, immunologically mediated disorder.

Taken together, there is strong scientific and programmatic rationale for this comprehensive effort to examine molecular and cellular mechanisms that underly the immune-mediated thrombocytopenias.

Insights and concepts derived from these basic studies should enhance the development of novel, clinically relevant diagnostic and therapeutic applications.

Versiti Wisconsin

THE DIVISION OF BLOOD DISEASES AND RESOURCES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE PATHOPHYSIOLOGY, DIAGNOSIS, TREATMENT, AND PREVENTION OF NON-MALIGNANT BLOOD DISEASES, INCLUDING ANEMIAS, SICKLE CELL DISEASE, THALASSEMIA, LEUKOCYTE BIOLOGY, PRE-MALIGNANT PROCESSES SUCH AS MYELODYSPLASIA AND MYELOPROLIFERATIVE DISORDERS, HEMOPHILIA AND OTHER ABNORMALITIES OF HEMOSTASIS AND THROMBOSIS, AND IMMUNE DYSFUNCTION. FUNDING ENCOMPASSES A BROAD SPECTRUM OF HEMATOLOGIC INQUIRY, RANGING FROM STEM CELL BIOLOGY TO MEDICAL MANAGEMENT OF BLOOD DISEASES AND TO ASSURING THE ADEQUACY AND SAFETY OF THE NATION'S BLOOD SUPPLY. PROGRAMS ALSO SUPPORT THE DEVELOPMENT OF NOVEL CELL-BASED THERAPIES TO BRING THE EXPERTISE OF TRANSFUSION MEDICINE AND STEM CELL TECHNOLOGY TO THE REPAIR AND REGENERATION OF HUMAN TISSUES AND ORGANS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Milwaukee, Wisconsin 53226 United States

Single Zip Code

NHLBI Program Project Applications (P01 Clinical Trials Optional) (PAR-21-088)

Amendment Since initial award the total obligations have increased 99% from $2,577,453 to $5,130,743.