R35HL155672

Impact of Infection and Inflammation on Primitive Hematopoiesis - Project Summary/Abstract

Hematopoietic stem cells (HSCs) in the bone marrow are responsible for the regulated production of about ten billion blood cells per day. Inflammation plays a key role in HSC function, promoting increased production of immune cells during conditions of stress or infection. However, Dr. King’s prior work has shown that prolonged exposure to interferon gamma, induced during chronic mycobacterial infections, alters HSC self-renewal and differentiation, ultimately leading to HSC depletion and pancytopenia.

This discovery spawned an explosion in research into the connections between inflammation and primitive hematopoiesis and the role of inflammation in bone marrow failure syndromes, hematologic malignancies, and age-associated impaired immunity. Despite its disease relevance, fundamental questions remain about the mechanisms by which inflammation releases HSCs from quiescence and promotes differentiation, and the hematologic and immunologic consequences of these changes.

The proposed research program builds upon the PI’s productive research track record to delineate the molecular, transcriptional, and epigenetic mechanisms by which inflammation regulates primitive hematopoiesis. Dr. King has identified key molecular mediators of inflammation-induced HSC differentiation, including the transcription factor BATF2 and the cell surface adhesin BST2, highlighting how both cell intrinsic transcriptional changes and cell extrinsic alterations in cell-cell interactions contribute to altered HSC activity upon inflammation. Furthermore, Dr. King has extrapolated this work to show how a mutation in the epigenetic modifier DNMT3A impairs inflammation-induced differentiation of HSCs and thereby contributes to clonal hematopoiesis, a widespread phenomenon linked to heart disease, stroke, and increased mortality in the elderly.

Building on this groundbreaking work, the proposed research program is divided into three projects. The first project will delineate the mechanism of action of BATF2 and BST2 in inflammation-mediated HSC differentiation. These mechanistic studies will provide potential therapeutic targets to preserve HSC function in the setting of chronic inflammation. The second project will quantify the impact of HSC differentiation on clonal competition in order to provide critical insight into infection and inflammation as an environmental contributor to clonal hematopoiesis, which is a risk factor for leukemia and cardiovascular disease. Finally, the third project will ascertain the importance of inflammation-induced transcription and epigenetic changes in HSCs to immunity. These studies will elucidate how inflammatory regulation of HSCs contributes to the formation and function of immune effector cells.

Collectively, the proposed research program defines the impact of inflammatory cytokine signaling on HSCs, their longevity, and their ability to maintain a healthy blood and immune system over time. The long-term goal of these studies is to provide physiologic knowledge that will lead to new strategies to protect and enhance bone marrow function for patients with bone marrow failure, cancer, stem cell transplant, and chronic inflammatory conditions, as well as for the aging population at large.

Baylor College Of Medicine

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]

Houston, Texas 770303411 United States

Single Zip Code

NHLBI Emerging Investigator Award (EIA) (R35 Clinical Trial Optional) (RFA-HL-20-012)

Amendment Since initial award the total obligations have increased 399% from $859,050 to $4,290,831.