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

基本信息

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
项目类别：
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

项目摘要

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）：作为一名医师科学家，我的目标是进行实验室研究，以推进该领域的发展，并改善对患者的护理。我在传染病和重症监护医学方面的背景相结合，为我提供了研究脓毒症临床问题的独特视角。我将花费大约 75% 的时间进行科学研究，其余时间作为重症监护病房的重症监护人员，这将加强我对脓毒症研究的关注。 K08 奖将使我能够扩大对脓毒症期间共刺激受体免疫反应调节的研究，并研究共刺激分子表达的调节作为脓毒症患者定制免疫治疗的潜在形式。在此期间，我将进一步发展我的研究生涯：1）参加每周的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 IDSA、SCCM 和 Shock Society 会议并介绍我的工作。我的长期目标是获得 RO1 级别的资助，并从指导研究环境过渡到独立研究者。该项目将研究共刺激分子 (CSM) 在脓毒症期间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 在确定免疫反应动态和脓毒症宿主存活方面的作用尚未明确。 TLR 通过识别微生物产物充当感染的早期检测器，并通过刺激炎症细胞因子的释放和抗原呈递细胞 (APC) 上的 CSM 上调来帮助启动免疫反应。最近的研究表明，腺苷受体能够调节 APC 和淋巴细胞上的 CSM 表达。我们的研究小组发现，缺乏腺苷 2A 或 2B 受体或接受 A2BR 药物阻断的脓毒症小鼠的感染清除率和生存率有所提高。使用经过充分表征的盲肠结扎穿刺脓毒症小鼠模型 (CLP)，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、和 T 细胞增殖和效应器功能，2) 确定单独或联合激活或阻断特定 TLR 和腺苷受体是否会改变 CSM 表达并改善脓毒症 CLP 模型中的感染清除和存活， 3) 确定直接操纵 CSM 表达是否可以改善脓毒症期间的免疫功能，从而减少细菌负荷并提高存活率。这些实验将共同描述 CSM 在脓毒症免疫反应中的作用，并确定 CSM 表达的药理调节是否是一种潜在的治疗干预措施。