Adenosine and TLR regulation of costimulatory molecule expression in sepsis

腺苷和 TLR 对脓毒症共刺激分子表达的调节

• 批准号: 8839254
• 负责人: CATHERINE VALENTINE
• 金额: $ 16.2万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839254
• 关键词: ADORA2A gene; Acute; Adenosine; Affect; Aftercare; Agonist; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen-Presenting Cells; Antigens; Award; Body Temperature; Cardiac; Cardiovascular Physiology; Caring; Cell Count; Cell Surface Proteins; Cell physiology; Clinical; Clinical Markers; Communicable Diseases; Complex; Critical Care; Data; Dendritic Cells; Development; Environment; Evolution; Flow Cytometry; Funding; Goals; Hospitals; Immune response; Immunology; Immunosuppression; Immunotherapy; Incidence; Individual; Infection; Inflammatory; Inflammatory Response; Intensive Care Units; Interleukin-6; Laboratory Research; Ligands; Ligation; Lipopolysaccharides; Lymphocyte; Measurement; Measures; Mediating; Medical; Medicine; Mentors; Microbe; Modeling; Monitor; Mus; Myocardial dysfunction; Outcome; Patients; Pattern; Peripheral Blood Lymphocyte; Peritoneal; Peritoneal Macrophages; Peritoneum; Physicians; Plasma; Play; Puncture procedure; Purinergic P1 Receptors; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Research; Research Personnel; Role; Scientist; Sepsis; Shock; Signal Pathway; Signal Transduction; Societies; Spleen; Syndrome; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; TLR4 gene; Testing; Therapeutic Intervention; Time; Toll-like receptors; Training; Up-Regulation; Weight Gain; Work; adenosine receptor activation; career; cytokine; detector; immune function; improved; microbial; mortality; mouse model; peripheral blood; receptor; receptor function; research study; response; septic; skills; symposium; theories; therapeutic target; treatment effect

DESCRIPTION (provided by applicant): My goals as a physician-scientist are to perform laboratory research that will advance the field, and improve the care of my patients. The combination of my background in Infectious Disease and Critical Care medicine gives me unique perspective from which to study the clinical problem of sepsis. I will spend approximately 75% of my time pursuing scientific research, and the remainder as a critical care attending in the intensive care units which will reinforce my focus on studies of sepsis. The K08 award will enable me to expand my studies of regulation of the immune response by costimulatory receptors during sepsis and investigate the modulation of costimulatory molecule expression as a potential form of tailored immunotherapy for septic patients. During this time I will further develop my research career though: 1) participation in weekly immunology seminars and formal coursework; 2) augmentation of my technical skills by attending advanced training courses in flow cytometry; and 3) attendance and presentation of my work at IDSA, SCCM and Shock Society conferences. My long term objective is to obtain RO1 level funding and transition from a mentored research environment to independent investigator. The proposed project will investigate the mechanistic role of costimulatory molecules (CSM) in the immune response during sepsis, and the ability of Toll-like (TLR) and adenosine receptor mediated activity to regulate expression of these molecules. The role of CSM to determine the dynamics of the immune response and survival of the septic host has not been defined. TLRs function as early detectors of infection through recognition of microbial products and help initiate an immune response through stimulating the release of inflammatory cytokines and upregulation CSM on antigen presenting cells (APCs). Recent work has shown that adenosine receptors have the capacity to modulate CSM expression on APCs and lymphocytes. Our group has found that septic mice lacking the adenosine 2A or 2B receptor or who receive pharmacologic blockade of A2BR have improved clearance of infection and survival. Using a well characterized mouse model of sepsis of cecal ligation and puncture (CLP) we will 1) Study the expression of different CSM longitudinally in septic mice and determine their association with pro and anti-inflammatory cytokine levels in plasma, ability to clear infection, and T cell proliferation and effector function, 2) Determine if activating or blocking specific TLRs and adenosine receptors singly, or in combination alters CSM expression and improves clearance of infection and survival in a CLP model of sepsis, and 3) Determine if direct manipulation of CSM expression improves immune function during sepsis to decrease bacterial load and increase survival. Together these experiments will characterize the role of CSM in the immune response to sepsis, and determine if pharmacologic modulation of CSM expression is a potential therapeutic intervention.

描述（由申请人提供）：我的目标是作为一个医生，科学家进行实验室研究，将推进该领域，并改善我的病人的护理。我在感染性疾病和重症监护医学的背景相结合，给我独特的角度来研究脓毒症的临床问题。我将花费大约75%的时间进行科学研究，其余时间在重症监护室担任重症监护，这将加强我对败血症研究的关注。K 08奖将使我能够扩展我在脓毒症期间通过共刺激受体调节免疫反应的研究，并研究共刺激分子表达的调节作为脓毒症患者定制免疫疗法的潜在形式。在此期间，我将进一步发展我的研究生涯，但：1）参加每周免疫学研讨会和正式课程; 2）通过参加流式细胞术高级培训课程增强我的技术技能; 3）出席并介绍我在IDSA，SCCM和休克协会会议上的工作。我的长期目标是获得RO 1级资金，并从指导研究环境过渡到独立调查员。该项目将研究共刺激分子（CSM）在脓毒症免疫反应中的机制作用，以及Toll样（TLR）和腺苷受体介导的活性调节这些分子表达的能力。CSM的作用，以确定动态的免疫反应和生存的脓毒症主机尚未确定。TLR通过识别微生物产物作为感染的早期检测器，并通过刺激炎性细胞因子的释放和上调抗原呈递细胞（APC）上的CSM来帮助启动免疫应答。最近的研究表明，腺苷受体具有调节CSM在APC和淋巴细胞上表达的能力。我们的研究小组发现，缺乏腺苷2A或2B受体或接受A2 BR药物阻断的脓毒症小鼠的感染清除率和存活率有所提高。使用经过充分表征的盲肠结扎穿孔（CLP）脓毒症小鼠模型，我们将1）纵向研究脓毒症小鼠中不同CSM的表达，并确定它们与血浆中促炎和抗炎细胞因子水平、清除感染的能力以及T细胞的相关性细胞增殖和效应器功能，2）确定是否单独激活或阻断特定TLR和腺苷受体，或组合改变CSM表达并改善感染的清除和脓毒症CLP模型中的存活，和3）确定CSM表达的直接操作是否改善脓毒症期间的免疫功能以降低细菌负荷并增加存活。这些实验将共同表征CSM在脓毒症免疫应答中的作用，并确定CSM表达的药理学调节是否是潜在的治疗干预。