Hematopoietic Stem Cell Dysfunction and Regeneration in Severe Infection

严重感染时造血干细胞功能障碍和再生

• 批准号: 10598451
• 负责人: KATHERINE C. MACNAMARA
• 金额: $ 40.5万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598451
• 关键词: Acute; Antibiotic Resistance; Biological; Blood; Blood Platelets; Blood Vessels; Bone Marrow; Cells; Communicable Diseases; Disease; Erythrocytes; Exhibits; Functional disorder; Goals; Health; Hematopoiesis; Hematopoietic stem cells; Hemostatic function; Hospital Mortality; Host Defense; Immune; Immune System Diseases; Immune system; Impaired cognition; Impairment; Infection; Inflammation; Inflammatory; Life; Modeling; Natural regeneration; Organ failure; Outcome; Patients; Play; Positioning Attribute; Process; Production; Recovery; Research; Role; Sepsis; Shock; Stress; Survivors; System; Systemic infection; Testing; Tick-Borne Infections; Time; Tissues; Vaccines; Vascular Diseases; acute infection; burden of illness; clinically significant; improved; improved outcome; insight; mortality; mortality risk; programs; stem cell function; tissue regeneration; vector-borne pathogen

Project Summary Survivors of severe infection often exhibit prolonged immune dysfunction, physical and cognitive decline, and significantly elevated risk of mortality. How to improve long-term outcomes of survivors of severe infection is of major clinical significance and represents an important open question. Here, we will explore the long-term impact of shock-like infection, using models of tick-born infection and sepsis, on hematopoietic stem cell (HSC) function by asking: What are the long-term impacts of severe infection on hematopoiesis and HSC function? Are HSCs primed to produce particular lineages? Can we protect HSCs in severe disease to improve outcomes in survivors? How is the bone marrow microenvironment (or niche), where HSCs reside, impacted by severe disease? Sepsis is a severe systemic infection that causes vascular dysfunction and organ failure, and represents a major cause of mortality in hospitals. Despite advances in understanding of sepsis pathophysiology, treatments are limited, and mortality remains high. At the same time, antibiotic resistance, the spread of vector born pathogens, and the lack of vaccines for emerging infections are important factors in the global increase in infectious disease burden. As serious infections continue to emerge and rates of sepsis have increased, so has the number of survivors. Here, we aim to understand the biological impact of severe, acute infection on the function of HSCs and hematopoiesis during recovery, to provide new insight into the decline in health after serious infection. Continuous and balanced blood production relies on HSCs and progenitors and is essential for life. The process of blood production generates cells of the immune system critical for host defense, as well as all blood components necessary for oxygenation (red blood cells) and vascular hemostasis (platelets). HSCs are positioned at the top of the blood system hierarchy, held in reserve, but can be activated by acute inflammation to produce immune cells. What is unknown is how acute inflammatory insults impact stem cell function in the long-term stages of recovery. In addition to immune cells, blood components (RBCs and platelets) play underappreciated roles in host defense and are important for regeneration and function of all tissue systems. Ultimately, we will test strategies to improve the number and function of stem cells in survivors of severe infectious illness.

项目概要 严重感染的幸存者往往表现出长期的免疫功能障碍、身体和认知能力下降， 以及死亡风险显着升高。如何改善重症幸存者的长期结果 感染具有重要的临床意义，也是一个重要的悬而未决的问题。在这里，我们将探索 使用蜱传感染和败血症模型研究休克样感染对造血的长期影响 通过询问以下问题来了解干细胞 (HSC) 的功能：严重感染对造血功能的长期影响是什么 和HSC功能？ HSC 是否准备好产生特定的谱系？在严重的情况下我们能保护HSC吗？ 疾病以改善幸存者的结果？骨髓微环境（或生态位）如何，在哪里 HSC 存在，受到严重疾病的影响吗？ 脓毒症是一种严重的全身感染，可导致血管功能障碍和器官衰竭，是一种严重的全身性感染。 医院死亡的主要原因。尽管对脓毒症病理生理学的理解取得了进展， 治疗方法有限，死亡率仍然很高。与此同时，抗生素耐药性的蔓延 媒介传播的病原体以及缺乏针对新发感染的疫苗是全球疫情的重要因素 传染病负担增加。随着严重感染的不断出现和败血症的发生率 增加了，幸存者的数量也增加了。在这里，我们的目标是了解严重的生物学影响， 急性感染对恢复期间 HSC 和造血功能的影响，为研究急性感染提供新的见解 严重感染后健康状况下降。 持续和平衡的血液生产依赖于造血干细胞和祖细胞，对生命至关重要。这 血液生产过程产生对宿主防御至关重要的免疫系统细胞，以及所有 氧合（红细胞）和血管止血（血小板）所需的血液成分。 HSC 位于血液系统层次结构的顶部，处于储备状态，但可以通过以下方式激活： 急性炎症产生免疫细胞。目前尚不清楚的是急性炎症损伤如何影响 干细胞在长期恢复阶段的功能。除了免疫细胞之外，还有血液成分 （红细胞和血小板）在宿主防御中发挥着未被充分认识的作用，并且对再生很重要 和所有组织系统的功能。最终，我们将测试改进数量和功能的策略 严重传染病幸存者的干细胞。

项目成果

Bone Marrow Harbors a Unique Population of Dendritic Cells with the Potential to Boost Neutrophil Formation upon Exposure to Fungal Antigen.

• DOI: 10.3390/cells11010055
• 发表时间: 2021-12-24
• 期刊: Cells
• 影响因子: 6
• 作者: Goedhart M;Slot E;Pascutti MF;Geerman S;Rademakers T;Nota B;Huveneers S;Buul JDV;MacNamara KC;Voermans C;Nolte MA
• 通讯作者: Nolte MA