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Improving Inflammation Resolution to Mitigate Acquired Bone Marrow Failure

改善炎症消退以减轻获得性骨髓衰竭

基本信息

批准号：
10595109
负责人：
KATHERINE C. MACNAMARA
金额：
$ 51.58万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595109
关键词：
Address Alternative Therapies Aplastic Anemia Autoimmune Diseases Behavior Biological Biological Assay Blood Bone Marrow Bone Marrow Transplantation Bone marrow failure CD47 gene Cell Surface Receptors Cells Chronic Data Disease Effectiveness Elderly Equilibrium Failure GPR18 receptor Generations Health Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Host Defense Human Immune Immunosuppression Impairment Infection Inflammation Inflammation Process Inflammatory Inflammatory Response Kinetics Knowledge Leukotrienes Life Macrophage Marrow Mediating Mediator Mission Molecular Mus Natural regeneration Omega-3 Fatty Acids Organism Outcome PTPNS1 gene Pathogenesis Pathway interactions Patients Physiological Predisposition Production Prostaglandins Recovery Refractory Resolution Role Series Testing Therapeutic Therapeutic immunosuppression Time Transgenic Mice Transplantation United States National Institutes of Health Work acquired bone marrow failure aged bone marrow failure syndrome burden of illness cell injury hematopoietic stem cell self-renewal human disease improved insight lipid mediator mortality mouse model new therapeutic target novel novel strategies novel therapeutics older patient prevent programs receptor receptor expression reparative process standard of care stem cell function survival outcome transplantation therapy

项目摘要

Improving Inflammation Resolution to Mitigate Acquired Bone Marrow Failure Bone marrow failure is the devastating collapse of blood production, and current treatments are inadequate. First line therapies include immunosuppressive therapies, and when feasible, bone marrow transplantation. These therapies are often efficacious in the short-term, especially for young patients, however they are much less effective in older patients. Immune suppression is not well tolerated, especially in the elderly, and carries increased susceptibility to infection. Therefore, alternative therapies are needed. It is well established that bone marrow failure is associated with non-resolving inflammation. The resolution of inflammation requires the balance between pro-inflammatory leukotrienes or prostaglandins and w3-derived specialized pro-resolving mediators (SPMs), like resolvins. Using a mouse model of acquired severe aplastic anemia (SAA) that mirrors key features of human disease, we established a role for impaired inflammation resolution programs in disease pathogenesis. Our preliminary work demonstrates the effectiveness of SPMs in ameliorating SAA. The rationale for the proposed work is that rather than blunting inflammatory responses, promoting resolution and reparative processes may be an ideal therapeutic strategy for bone marrow failure. The proposed studies will address a fundamental gap in our understanding of the physiologically relevant process of inflammation resolution in the bone marrow. We propose three integrated, but independent, Aims to: (1) address mechanisms of impaired resolution, (2) determine the impact of SPMs in the marrow in SAA, and (3) evaluate the effect of SPMs on function of hematopoietic stem cells. The proposed work will support a novel approach to treat BMF without the use of immune suppression, representing an important departure from the current standard of care. We believe these studies will be impactful therapeutic options for BMF patients, particularly older patients where IST has failed, and wherein host defenses are already weakened. At the same time, the proposed studies may provide new mechanistic insight relevant to other diseases characterized by prolonged and non-resolved inflammation, and thus will have broad impact to human health.

改善炎症消退以减轻获得性骨髓衰竭