R35HL161239

Immune Pathophysiology of Sickle Cell Disease - Project Abstract

A chronic inflammatory state is now considered a hallmark of sickle cell disease (SCD) resulting from ongoing hemolytic insult to the underlying vasculature and repeated cycles of vaso-occlusion crisis (VOC).

Transfusions remain a cornerstone treatment for patients with SCD, but unlike other transfused patient populations, a higher proportion (20-50%) of patients with SCD develop alloantibodies with potentially life-threatening sequelae. These include poorly understood delayed transfusion reactions (DHTRS) whose occurrence, as well as clinical progression from mild to severe, is unpredictable.

A long-standing interest of our research program has been to understand the underlying immune mechanisms leading to SCD complications including VOC and transfusion complications. Our studies have uncovered an underappreciated role of circulating monocytes and the innate immune response to hemolysis, a hallmark of SCD, in transfusion complications including alloimmunization and DHTRS.

Our projected studies as part of this R35 will be focused on innate immune cellular pathways that magnify the inflammatory SCD state versus the cells' heme protective pathways such as the heme detoxifying key enzyme heme oxygenase 1 in alloimmunization and in the development of DHTRS.

Our laboratory has also identified a novel function for a subset of circulating monocytes, referred to as patrolling monocytes (PMO), in their ability to scavenge and remove damaged endothelium and endothelial-attached sickle red blood cells (RBCs). The discovery of a novel mechanism of action of PMO in SCD offers a paradigm shift in our understanding of VOC and opens up the possibility that PMOs can be manipulated to prevent painful VOC.

An objective of the proposed studies in this R35 is to understand the mechanisms by which PMO protect SCD vasculature and how they are affected both functionally and numerically during a vaso-occlusive event with the goal to help establish their role in VOC pathophysiology, and their potential as a therapeutic target for VOC.

As we have done in the past, all the proposed studies for both objectives will combine the use of in vivo mouse models, in vitro human model systems, and patient samples to mechanistically dissect in a rigorous manner how specific immune cell types and molecular pathways contribute to SCD alloimmunization and VOC.

Altogether, we believe that our laboratory's approach of integrating studies in humans and experimental models to mechanistically dissect immune pathways that regulate SCD complications is likely to be impactful and generate novel findings in areas critical to the NHLBI scientific mission.

New York Blood Center

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]

New York, New York 10065 United States

Single Zip Code

NHLBI Outstanding Investigator Award (OIA) (R35 Clinical Trial Optional) (RFA-HL-20-011)

Amendment Since initial award the total obligations have increased 324% from $846,806 to $3,589,657.