Alcohol, Septicemia and the LKS Cell Response

酒精、败血症和 LKS 细胞反应

基本信息

批准号：
8644759
负责人：
PING ZHANG
金额：
$ 19.62万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-10 至 2015-04-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8644759
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

项目摘要

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.

描述（由申请人提供）：酒精是最常见的滥用药物，使宿主容易受到细菌感染。患有严重细菌感染的酒精性患者，尤其是败血病，通常出现粒细胞减少症，这是死亡率增加的指标。为了响应细菌感染，正常个体的骨髓会以其他谱系发育为代价增加粒细胞的产生，以增强宿主防御入侵病原体的防御。我们最近的研究表明，在败血症血症期间，谱系（LIN）-C-KIT+ SCA-1+细胞（LKS细胞，富集的造血干细胞种群）迅速扩大。原始造血前体的这种改变在颗粒反应中起着关键作用。 LIN-C-KIT+SCA-1-细胞（主要是髓样祖细胞）的SCA-1是负责LIN-C-KIT+SCA-1+细胞池快速扩张的主要机制。 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。酒精中毒会损害细菌感染期间LIN-C-KIT+ SCA-1+细胞群的扩张。目前，尚无有关酒精造成颗粒颗粒反应初始阶段的机制的信息。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，酒精抑制了介导LIN-C-KIT+ SCA-1+细胞反应中涉及的关键细胞信号通路，并损害败血症期间骨髓中粒细胞产生的初始激活。这三个具体目的是：1。测试酒精抑制原始造血前体细胞对髓样谱系发育的承诺，以响应败血症，从而损害SCA-1/TLR4-PU.1途径； 2。测试假说，即酒精通过LIN-C-KIT+SCA-1-细胞抑制SCA-1的表达，以响应败血症，从而损害TLR4-JNK-AP1途径。 3。检验以下假设：酒精抑制LIN-C-KIT+ SCA-1+细胞增殖的激活对败血病的反应，通过损害TLR4-P44/42-Cyclin d途径。从这项研究中获得的结果将填补我们的知识，即在酗酒者中造血的造血干细胞/祖细胞水平上宿主防御的损害。它还将构成开发新型治疗干预措施以治疗这些免疫功能低下宿主中严重感染的基础。