Alcohol, hedgehog signal, and HSC dysfunction in host defense against septicemia

酒精、刺猬信号和 HSC 功能障碍在宿主防御败血症中的作用

• 批准号: 9315570
• 负责人: PING ZHANG
• 金额: $ 34.11万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315570
• 关键词: Address; Adult; Agranulocytosis; Alcohol abuse; Alcohols; Alpha Cell; Antigens; Attenuated; Bacterial Infections; Bone Marrow; Bone Marrow Cells; Cause of Death; Cell Proliferation; Cell physiology; Cells; Cyclin D1; Development; ETS Family Protein; Embryonic Development; Emergency Situation; Escherichia coli; Functional disorder; GLI gene; Glioma; Hematopoietic; Hematopoietic stem cells; Host Defense; Immune; Immunocompromised Host; Impairment; Infection; Investigation; Knowledge; Leukopenia; MAPK3 gene; Marrow; Mediating; Mus; PTCH gene; Pathway interactions; Patients; Population; Proteins; Proto-Oncogene Protein c-kit; Regulation; Reporting; SHH gene; SPI1 gene; Septicemia; Signal Transduction; Specificity; Stem cells; System; Systemic infection; TLR4 gene; Testing; Time; United States; Up-Regulation; Zinc Fingers; alcohol abuser; alcohol effect; alcohol exposure; effective therapy; experimental study; extracellular signal-regulated kinase 4; granulocyte; hedgehog signal transduction; mortality; novel therapeutic intervention; precursor cell; problem drinker; public health relevance; response; smoothened signaling pathway; stem; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Alcohol abusers are susceptible to bacterial infection. Alcoholic patients with serious infection, particularly septicemia, frequently present with granulocytopenia which is an indicator for increased mortality. Our recent studies have revealed that in response to bacterial infection, bone marrow pool of lineage(lin)-stem cell factor receptor(ckit)+stem cell antigen-1(Sca1)+ cells (LKS cells, a cell population enriched with hematopoietic stem cells) is rapidly increased in mice. The emergency expansion of LKS cell population is associated with reprogramming of these primitive precursors to enhance their commitment to granulocyte lineage development. Alcohol impairs this critical step of the granulopoietic response. At the present time, the underlying cell signaling mechanisms remain unclear. The hedgehog signal transduction pathway has been reported to participate in the regulation of certain stem/progenitor cell functions in normal state during embryogenesis and in adulthood. In preliminary experiments, we observed that Sonic hedgehog (SHH) expression was significantly up-regulated in the bone marrow of mice with septicemia. The Toll-like receptor (TLR)4-extracellular signal-regulated kinases (ERK)1/2-specificity protein 1(Sp1) signal cascade provided the essential signal for up-regulation of SHH expression by marrow cells. LKS cells were the most active cells responding to SHH. Activation of SHH-glioma zinc finger transcription factor 1 (Gli1)-cyclin D1 signaling promoted LKS cell proliferation, whereas activation of SHH-Gli1-PU.1 (an ETS-domain transcription factor encoded by the SPI1 gene) signaling mediated LKS cell reprogramming for enhanced commitment to granulocyte lineage development. Alcohol exposure disrupted this signaling system. Therefore, we propose to systematically investigate the effects of alcohol on SHH signaling in the regulation of primitive hematopoietic precursor cell activation during the granulopoietic response to septicemia. Our central hypothesis is that alcohol impairs primitive hematopoietic precursor cell function during the granulopoietic response to systemic infection by disrupting SHH signaling. Three specific aims are: 1) to test the prediction that alcohol inhibits activation of the SHH signal pathway in LKS cells in response to septicemia; 2) to test the prediction that alcohol inhibits LKS cell proliferation in response t septicemia via impairing the GLI1-cyclin D1 pathway; and 3) to test the prediction that alcohol inhibits LKS cell reprogramming for enhancing granulocyte lineage commitment during septicemia via impairing the Gli1-PU.1 signal cascade. Results obtained from this investigation will greatly advance our knowledge about the impairment of host defense against serious infections in alcohol abusers. It will also identify key targets for developing novel therapeutic interventions to treat fatal infections in these immunocompromised hosts.

描述（由申请人提供）：滥用酒精的人容易受到细菌感染的影响。患有严重感染的酒精性患者，尤其是败血病，经常出现粒细胞减少症，这是死亡率增加的指标。我们最近的研究表明，为了应对细菌感染，谱系（LIN） - 茎细胞因子受体（CKIT）+干细胞抗原1（SCA1）+细胞（LKS细胞，富含血肿干细胞的细胞种群）的骨髓库迅速增加。 LKS细胞种群的紧急扩张与这些原始前体的重编程有关，以增强其对粒细胞谱系发育的承诺。酒精会损害颗粒反应的关键步骤。目前，底层细胞信号传导机制尚不清楚。据报道，刺猬信号转导途径参与了胚胎发生和成年期在正常状态下的某些茎/祖细胞功能的调节。在初步实验中，我们观察到在败将的小鼠骨髓中，声音刺猬（SHH）的表达显着上调。 Toll样受体（TLR）4-纤维细胞信号调节激酶（ERK）1/2特异性蛋白1（SP1）信号级联为骨髓细胞上调SHH表达的基本信号。 LKS细胞是对SHH响应的最活跃的细胞。 SHH-糖锌指转录因子1（GLI1）-CRYCLIN D1信号传导的激活促进了LKS细胞的增殖，而SHH-GLI1-PU.1的激活（由SPI1基因编码的ETS-核心转录因子）的激活信号传导介导的LKS细胞重新编程，以增强对Granity linea的投入。酒精暴露破坏了该信号系统。因此，我们建议系统地研究酒精对原始造血前体细胞调节SHH信号的影响 在肉芽肿反应中对败血病的激活。我们的中心假设是，酒精通过破坏SHH信号传导而对全身感染的粒状反应期间造成原始造血前体细胞功能。三个具体目的是：1）测试酒精抑制败血症中LKS细胞中SHH信号途径的激活的预测； 2）测试酒精通过损害GLI1-循环D1途径而抑制LKS细胞增殖的预测； 3）测试酒精会抑制LKS细胞重编程以通过损害GLI1-PU.1信号级联反应来增强粒细胞谱系的预测的预测。从这项调查中获得的结果将大大提高我们对宿主防御对酗酒者严重感染的损害的了解。它还将确定开发新的治疗干预措施以治疗这些免疫功能低下宿主中致命感染的关键靶标。