Alcohol and Sca-1; Impairment of the granulopoietic precursor cell response

描述(由申请人提供)： 项目摘要/摘要：酗酒使宿主容易受到细菌感染。有严重细菌感染的酗酒者的一个显著特征是他们经常出现粒细胞减少症，这是死亡率增加的一个指标。粒细胞代表着体循环中最大的吞噬细胞群，构成了宿主抵御入侵病原体的第一道防线。为了应对细菌感染，骨髓会增加粒细胞的产生，以加强宿主对入侵病原体的防御。在这个过程中，原始的造血祖细胞被重新编程，以分化它们对粒细胞的谱系承诺。我们最近的研究表明，在败血症期间，骨髓中LIN-cKit+SCA-1+细胞(LKS细胞，一群浓缩的造血干细胞)的数量迅速增加。这种LKS细胞的反应主要是通过上调SCA-1的表达来支持的，而SCA-1的表达对于促进粒细胞的产生至关重要。酒精中毒会损害这种反应。我对这一应用的初步研究表明，在败血症期间，下游粒细胞系致力于表达低水平粒细胞分化抗原-1(Gr1)的细胞也会增强SCA-1的表达。SCA-1在这一特定细胞室的表达上调与粒系前体细胞的增殖和粒细胞的生成加速有关。这个过程涉及关键的细胞信号通路，下调STAT3信号，增强p44/p42-细胞周期蛋白D信号。酒精中毒扰乱了细胞信号活动的这些调节，并通过一种未知的机制损害了SCA-1相关的粒细胞产生的增强。基于这些初步研究，我的假设是酒精在粒细胞发育的早期阶段损害了SCA-1信号，并阻止了对败血症的粒系反应。两个特定的目的是：(1)检验酒精损害SCA-1介导的p44/42-Cyclin D信号增强促进败血症时Gr1lo细胞增殖的预测；(2)检验酒精破坏SCA-1介导的STAT3信号下调在败血症时调节Gr1lo细胞增殖的预测。这项研究将为酒精引起的细菌感染后粒系反应受损的分子机制提供新的信息。它还将为开发有效的治疗策略来治疗患有严重细菌感染的酒精滥用者的骨髓抑制奠定基础。 公共卫生相关性： 项目简介：了解酒精在败血症期间如何影响Gr1lo粒系前体细胞中SCA-1的表达，将为严重感染的酒精滥用者粒细胞减少的发病机制提供新的信息。酒精可能抑制了未知的内源性机制，即在感染期间扩大粒系前体细胞隔间并增强前体细胞的粒系活性。这项研究的信息将阐明有效治疗这些免疫受损宿主的血液传播感染的潜在治疗干预措施。

DESCRIPTION (provided by applicant): Project Summary/Abstract: Alcohol abuse predisposes the host to bacterial infections. A prominent feature of alcohol abusers with severe bacterial infection is that they frequently present with granulocytopenia, which is an indicator of increased mortality. Representing the largest population of phagocytes in the systemic circulation, granulocytes constitute the first line of host defense against invading pathogens. In response to bacterial infection, the bone marrow increases granulocyte production in order to reinforce host defense against invading pathogens. During this process, primitive hematopoietic precursor cells are reprogrammed to polarize their lineage commitment toward granulopoiesis. Our recent studies have revealed that the number of bone marrow lin-cKit+Sca-1+ cells (LKS cells, a population of enriched hematopoietic stem cells) is rapidly increased during septicemia. This LKS cell response is primarily supported by the up-regulation of Sca-1 expression, which is critical for the enhancement of granulocyte production. Alcohol intoxication impairs this response. My preliminary studies for this application show that Sca-1 expression during septicemia is also enhanced in downstream granulocyte lineage committed cells that express low levels of granulocyte differentiation antigen- 1 (Gr1). The up-regulated expression of Sca-1 in this committed cell compartment is associated with enhanced proliferation of granulopoietic precursors and accelerated production of granulocytes. This process involves key cell signaling pathways that down-regulate STAT3 signaling and enhance p44/p42-cyclin D signaling. Alcohol intoxication disrupts these adjustments in cell signaling activity and impairs Sca-1 associated enhancement of granulocyte production by an unknown mechanism. Based on these preliminary studies, my hypothesis is that alcohol impairs Sca-1 signaling in the early stage of granulocyte development and blocks the granulopoietic response to septicemia. Two specific aims are: (1) To test the prediction that alcohol impairs Sca-1 mediated enhancement of p44/42-cyclin D signaling in promoting Gr1lo cell proliferation during septicemia; (2) To test the prediction that alcohol disrupts Sca-1 mediated down- regulation of STAT3 signaling in the regulation of Gr1lo cell proliferation during septicemia. This study will provide novel information about the molecular mechanism underlying alcohol-induced impairment of the granulopoietic response to bacterial infection. It will also build a foundation for developing effective therapeutic strategies to treat myelosuppression in alcohol abusers with severe bacterial infection. PUBLIC HEALTH RELEVANCE: Project Narrative: Understanding how alcohol affects Sca-1 expression in Gr1lo granulopoietic precursor cells during septicemia will provide novel information about the pathogenesis of granulocytopenia in alcohol abusers with severe infection. Alcohol may be inhibiting yet unknown endogenous mechanisms that expand the granulopoietic precursor cell compartment and enhance the granulopoietic activity of precursor cells during infection. Information from this study will elucidate potential therapeutic interventions for the effective treatment of blood-borne infections in these immunocompromised hosts.