Alcohol, Septicemia and the LKS Cell Response

描述(申请人提供)：酒精是最常被滥用的药物，容易使宿主受到细菌感染。患有严重细菌感染，特别是败血症的酗酒患者经常出现粒细胞减少症，这是死亡率增加的一个指标。为了应对细菌感染，正常人的骨髓以牺牲其他血统发育为代价增加粒细胞的产生，以增强宿主对入侵病原体的防御。我们最近的研究表明，在败血症期间，LINE(LIN)-c-kit SCA-1细胞(LKS细胞，一种丰富的造血干细胞群体)的骨髓池迅速扩大。原始造血祖细胞的这种改变在粒系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是败血症后LIN-c-Kit Sca-1细胞库迅速扩大的主要机制。LIN-c-KIT SCA-1细胞增殖增强也是导致骨髓LIN-C-KIT SCA-1细胞数量增加的原因之一。酒精中毒损害了细菌感染过程中LIN-C-KIT SCA-1细胞群的扩张。目前，还没有关于酒精损害粒细胞反应初始阶段的机制的信息。在这个项目中，我们打算系统地探索潜在的细胞信号机制。我们的总体假设是，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，并在败血症时损害了骨髓中粒细胞产生的初始激活。三个具体目的是：1.验证酒精通过损害SCA-1/TLR4-PU.1通路而抑制原始造血祖细胞对髓系发育的承诺的假说；2.检验酒精通过损害TLR4-JNK-AP1通路而抑制LIN-c-KIT SCA-1细胞表达SCA-1的假说；3.检验酒精通过损害TLR4-P44/42-Cyclin D通路抑制败血症反应中LIN-c-KIT SCA-1细胞增殖的假说。这项研究的结果将填补我们对酒精滥用者在造血干细胞/祖细胞水平上对严重感染的宿主防御能力受损的认识的一个主要空白。它还将为开发新的治疗干预措施以治疗这些免疫受损宿主的严重感染奠定基础。

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.