Impact of Infection and Inflammation on Primitive Hematopoiesis

感染和炎症对原始造血的影响

• 批准号: 10647847
• 负责人: Katherine Yudeh King
• 金额: $ 86.14万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647847
• 关键词: Age; Aplastic Anemia; Bacterial Adhesins; Blood; Blood Cells; Bone Marrow; Bone marrow failure; Cardiovascular Diseases; Cell Communication; Cell surface; Cells; Chronic; Cytokine Signaling; DNMT3a; Disease; Dysmyelopoietic Syndromes; Effector Cell; Elderly; Epigenetic Process; Explosion; Exposure to; Genetic Transcription; Goals; Heart Diseases; Hematologic Neoplasms; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic stem cells; Immune; Immune system; Immunity; Immunologics; Impairment; Infection; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune Response; Interferon Type II; Knowledge; Life; Link; Longevity; Malignant Neoplasms; Mediating; Molecular; Mutation; Mycobacterium Infections; Pancytopenia; Patients; Physiological; Play; Production; Productivity; Regulation; Research; Risk Factors; Role; Stem cell transplant; Stress; Stroke; Time; Work; aging population; bone marrow failure syndrome; hematopoietic differentiation; hematopoietic stem cell differentiation; hematopoietic stem cell quiescence; hematopoietic stem cell self-renewal; immune function; insight; leukemia; mortality; preservation; programs; stem cell function; therapeutic target; transcription factor

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 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.

项目总结/文摘