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

• 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
• 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

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 骨髓衰竭是血液生产的毁灭性崩溃，目前的治疗方法是 不足一线治疗包括免疫抑制治疗，可行时，骨髓 移植这些疗法通常在短期内有效，特别是对年轻患者， 然而，它们对老年患者的效果要差得多。免疫抑制的耐受性不好， 尤其是在老年人中，并且增加了感染的易感性。因此，替代 需要治疗。骨髓衰竭与非消退性 炎症炎症的解决需要促炎和炎症反应之间的平衡。 白细胞三烯或白藜芦醇和W3衍生的特化促消退介质（SPM），如 消退素。使用获得性重型再生障碍性贫血（SAA）的小鼠模型， 人类疾病，我们建立了受损的炎症解决方案在疾病中的作用， 发病机制我们的初步工作证明了SPM在改善SAA方面的有效性。的 提出这项工作的理由是， 解决和修复过程可能是骨髓衰竭的理想治疗策略。的 拟议的研究将解决我们对生理相关性的理解中的一个根本性的空白。 骨髓中炎症消退的过程。我们提出三个一体化，但独立， 目的是：（1）解决受损分辨率的机制，（2）确定SPM在 （3）观察SPM对SAA骨髓造血干细胞功能的影响。 拟议的工作将支持一种新的方法来治疗BMF，而不使用免疫抑制， 这与目前的护理标准有很大的不同。我们相信这些研究将 为BMF患者提供有效的治疗选择，特别是IST失败的老年患者， 宿主的防御已经被削弱了与此同时，拟议的研究可能提供 与其他疾病相关的新机制见解，其特征是长期和未解决 炎症，因此将对人类健康产生广泛影响。