Alcohol, Septicemia and the LKS Cell Response

酒精、败血症和 LKS 细胞反应

• 批准号: 8267738
• 负责人: PING ZHANG
• 金额: $ 34.7万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-10 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267738
• 关键词: Address; Agranulocytosis; Alcohol abuse; Alcoholic Intoxication; Alcohols; Antigens; Attenuated; Bacterial Infections; Bone Marrow; Cause of Death; Cell Lineage; Cell Proliferation; Cells; Cyclin D1; Development; Foundations; Granulopoiesis; Health; Hematopoietic; Hematopoietic stem cells; Host Defense; Immunocompromised Host; Impairment; Individual; Infection; Invaded; Investigation; Knowledge; Leukopenia; Lipopolysaccharides; Marrow; Mediating; Myelogenous; N-terminal; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Play; Population; Production; Proto-Oncogene Protein c-kit; Role; Septicemia; Signal Pathway; Signal Transduction; Staging; Stem cells; Testing; Therapeutic; Time; Transcription Factor AP-1; United States; effective therapy; granulocyte; injured; mortality; novel therapeutic intervention; pathogen; precursor cell; problem drinker; progenitor; proto-oncogene protein Spi-1; public health relevance; research study; response; stem; stem cell population; stress-activated protein kinase 1; toll-like receptor 4

DESCRIPTION (provided by applicant): Alcohol is the most frequently abused drug that predisposes the host to bacterial infections. Alcoholic patients with severe bacterial infections, particularly septicemia, often present with granulocytopenia which is an indicator of increased mortality. In response to bacterial infection, the bone marrow of normal individuals increases granulocyte production at the expense of other lineage development in order to enhance host defense against invading pathogens. Our recent studies have revealed that the marrow pool of lineage(lin)-c- kit+Sca-1+ cells (LKS cells, an enriched hematopoietic stem cell population) is rapidly expanded during septicemia. This alteration of primitive hematopoietic precursors plays a key role in the granulopoietic response. Expression of Sca-1 by lin-c-kit+Sca-1- cells (primarily myeloid progenitors) is the major mechanism responsible for the rapid expansion of lin-c-kit+Sca-1+ cell pool following septicemia. Enhanced proliferation of lin-c-kit+Sca-1+ cells also contributes to the increase in the marrow lin-c-kit+Sca-1+ cell population. Alcohol intoxication impairs the expansion of the lin-c-kit+Sca-1+ cell population during bacterial infection. At the present time, no information is available about the mechanisms by which alcohol injures this initial stage of the granulopoietic response. In this project, we propose to systematically explore the underlying cell signaling mechanisms. Our overall hypothesis is that alcohol suppresses key cell signaling pathways involved in mediating the lin-c-kit+Sca-1+ cell response and impairs initial activation of granulocyte production in the bone marrow during septicemia. The three Specific Aims are: 1. To test the hypothesis that alcohol inhibits primitive hematopoietic precursor cell commitment to myeloid lineage development in response to septicemia via impairing the Sca-1/TLR4-PU.1 pathway; 2. To test the hypothesis that alcohol inhibits expression of Sca-1 by lin-c-kit+Sca-1- cells in response to septicemia via impairing the TLR4-JNK-AP1 pathway; 3. To test the hypothesis that alcohol inhibits activation of lin-c-kit+Sca-1+ cell proliferation in response to septicemia via impairing the TLR4-p44/42-cyclin D pathway. Results obtained from this investigation will fill a major gap in our knowledge regarding the impairment of host defense against serious infections at the level of hematopoietic stem/progenitor cells in alcohol abusers. It will also form a foundation for developing novel therapeutic interventions to treat serious infections in these immunocompromised hosts. PUBLIC HEALTH RELEVANCE: Alcohol abuse predisposes the host to severe bacterial infection which is one of the leading causes of death in the United States. Many alcoholic patients with severe bacterial infection present with leukopenia, which is frequently fatal. This project investigates the mechanisms underlying this serious health problem and will help to identify therapeutic approaches for effective treatment of alcoholic patients with severe bacterial infection.

描述（由申请人提供）：酒精是最常被滥用的药物，使宿主容易受到细菌感染。伴有严重细菌感染的酗酒患者，特别是败血症患者，常伴有粒细胞减少症，这是死亡率增加的一个指标。在对细菌感染的反应中，正常个体的骨髓增加了粒细胞的产生，以牺牲其他谱系的发育为代价，以增强宿主对入侵病原体的防御。我们最近的研究表明，谱系(lin)-c- kit+Sca-1+细胞（LKS细胞，一种富集的造血干细胞群）的骨髓池在败血症期间迅速扩大。这种原始造血前体的改变在粒细胞生成反应中起着关键作用。lin-c-kit+Sca-1-细胞（主要是髓系祖细胞）表达Sca-1是导致败血症后lin-c-kit+Sca-1+细胞池快速扩增的主要机制。lin-c-kit+Sca-1+细胞的增殖增强也有助于骨髓lin-c-kit+Sca-1+细胞群的增加。在细菌感染期间，酒精中毒会损害lin-c-kit+Sca-1+细胞群的扩增。目前，还没有关于酒精损害这一初始阶段的粒细胞生成反应的机制的信息。在这个项目中，我们建议系统地探索潜在的细胞信号传导机制。我们的总体假设是，在败血症期间，酒精抑制了参与介导lin-c-kit+Sca-1+细胞反应的关键细胞信号通路，并损害了骨髓中粒细胞产生的初始激活。三个具体目标是：1。为了验证酒精通过损害Sca-1/TLR4-PU抑制败血症反应中原始造血前细胞对髓系谱系发育的承诺的假设。1通路;2. 为了验证酒精通过损害TLR4-JNK-AP1通路抑制lin-c-kit+Sca-1-细胞在败血症反应中表达Sca-1的假设；3. 为了验证酒精通过损害TLR4-p44/42-cyclin D通路抑制lin-c-kit+Sca-1+细胞增殖在败血症反应中的激活的假设。这项研究的结果将填补我们在酗酒者造血干细胞/祖细胞水平上对严重感染的宿主防御受损的知识的主要空白。它还将为开发新的治疗干预措施以治疗这些免疫功能低下宿主的严重感染奠定基础。