Characterization of lymphatic contraction during infection

感染期间淋巴收缩的特征

• 批准号: 8422972
• 负责人: TIMOTHY P PADERA
• 金额: $ 21.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8422972
• 关键词: Address; Admission activity; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antigen-Presenting Cells; Antigens; Applications Grants; Area; Autoimmune Diseases; Bacteria; Bacterial Infections; Bacterial Toxins; Biochemistry; Biological; Biology; Blood Circulation; Bone Marrow; Bone Marrow Transplantation; CD8B1 gene; Cells; Cellular biology; Cellulitis; Chronic; Data; Development; Disease; Effectiveness; Ensure; Environment; Flow Cytometry; Fluid Balance; General Hospitals; Goals; Green Fluorescent Proteins; Hospitals; ITGAM gene; Image; Imaging Techniques; Imaging technology; Immune response; Immunobiology; Immunofluorescence Immunologic; Immunology; Impairment; Infection; Infection Control; Infectious Skin Diseases; Inflammation; Intercellular Fluid; Intervention; Intravenous; Label; Laboratories; Lead; Lymph; Lymphatic; Lymphatic vessel; Lymphedema; Massachusetts; Measures; Methods; Modeling; Molecular Biology Techniques; Monoclonal Antibodies; Mus; Myelogenous; Nitric Oxide; Nitric Oxide Synthase; PECAM1 gene; PTPRC gene; Patients; Play; Production; Public Health; Relative (related person); Research; Research Project Grants; Resolution; Resources; Role; Route; Signal Transduction; Site; Staining method; Stains; Staphylococcal Infections; Suppressor-Effector T-Lymphocytes; System; Testing; Therapeutic; Tissues; Toxin; Transplantation Chimera; Work; base; cytokine; experience; human NOS2A protein; innovation; insight; intravital imaging; lymph nodes; medical schools; mouse model; mutant; novel; prevent; research and development; response; uptake; vaccine development

DESCRIPTION (provided by applicant): The overall goal of this Exploratory Development Research Grant is to investigate whether bacterial infections suppress lymphatic function and thus inhibit immune response. This will lend initial insight into new ways to manage difficult-to-resolve infections, many of which currently require intravenous antibiotic treatment that can lead to antibiotic resistant bacteria strains-another significant problem. The PI is an expert in lymphatic research, especially functional studies using novel intravital imaging technologies and animal models. He has assembled a first class team consisting of Dr. Dai Fukumura, an expert in nitric oxide biology, Dr. Nancy H. Ruddle, an expert in immunobiology, cytokines and autoimmune diseases and Dr. Jean C. Lee, an expert in s. aureus biology and vaccine development. This robust and experienced research team, along with the resources available in the Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, ensure an optimal environment for the innovative studies proposed in this EDRG. Initial lymphatic vessels take up interstitial fluid to create lymph that is transported through collecting lymphatic vessels and lymph nodes, and eventually returned to blood circulation to maintain tissue fluid balance. Antigen and antigen presenting cells (APC) use this route to enter the draining lymph node (LN) and initiate an immune response. Chronic infections, such as in cellulitis, are frequently associated with lymphedema, which is generally associated with malfunctions or disruptions in the function of collecting lymphatic vessels. Cases of cellulitis are responsible for nearly 400,000 hospital admission each year in the US. In this Exploratory Developmental Research Grant proposal we will test the hypothesis that these difficult-to-resolve infections are aided by an impairment of autonomous contraction of lymphatic vessels draining the infected area, thus limiting signaling to the lymph node and causing toxin accumulation at the site of infection. We will use our novel murine model that allows autonomous lymphatic contractions to be imaged and quantified intravitally. We will study the impairment of lymphatic function during s. aureus infection (Aim 1), the role of host derived nitric oxide from myeloid derived suppressor cells in causing lymphatic impairment (Aim 2) and the role of nitric oxide produced by the s. aureus nitric oxide synthase on lymphatic function (Aim 3). To achieve these Aims we will measure the strength of lymphatic contraction, lymphatic flow, antigen transport and duration of infection. We will characterize the biological response to the experimental conditions using standard cell biology, biochemistry and molecular biology techniques. These aims will enable us to address whether blocking nitric oxide is a therapeutic option to enhance the clearance of bacteria during s. aureus cellulitis. This EDRG proposal lies at the crossroads between immunology and functional lymphatic biology, an intersection that has been understudied to date. The work proposed here will drive this field by applying the principals of lymphatic function to study the important public health problem of s. aureus skin infections.

描述(由申请人提供)：这项探索性发展研究基金的总体目标是调查细菌感染是否会抑制淋巴功能，从而抑制免疫反应。这将使人们对管理难以解决的感染的新方法有了初步的了解，其中许多目前需要静脉注射抗生素治疗，这可能导致抗生素耐药细菌菌株--另一个重大问题。PI是淋巴研究的专家，特别是使用新的活体成像技术和动物模型进行功能研究的专家。他组建了一支一流的团队，成员包括一氧化氮生物学专家戴福村博士、免疫生物学、细胞因子和自身免疫性疾病专家南希·H·拉德尔博士，以及金黄色葡萄球菌生物学和疫苗开发专家让·C·李博士。这支强大而经验丰富的研究团队，加上埃德温·L·斯蒂尔实验室、马萨诸塞州综合医院和哈佛医学院提供的资源，确保了本EDRG建议的创新研究的最佳环境。最初的淋巴管吸收间质液体，产生淋巴，淋巴通过收集的淋巴管和淋巴结运输，最终返回血液循环，以维持组织液体平衡。抗原和抗原提呈细胞(APC)使用这一途径进入引流淋巴(LN)并启动免疫反应。慢性感染，如蜂窝织炎，经常与淋巴水肿有关，淋巴水肿通常与收集淋巴管的功能障碍或中断有关。在美国，蜂窝组织炎每年导致近40万人入院。在这项探索性发展研究拨款提案中，我们将检验这样一种假设，即这些难以解决的感染是由排出感染区域的淋巴管自主收缩的损害而帮助的，从而限制了向淋巴结发出的信号，并导致感染部位的毒素积累。我们将使用我们的新型小鼠模型，该模型允许在生命中对自主淋巴收缩进行成像和量化。我们将研究金黄色葡萄球菌感染期间淋巴功能的损害(目标1)，来自髓系抑制细胞的宿主来源的一氧化氮在导致淋巴损害中的作用(目标2)，以及金黄色葡萄球菌一氧化氮合酶产生的一氧化氮对淋巴功能的作用(目标3)。为了实现这些目标，我们将测量淋巴收缩、淋巴流动、抗原运输和感染持续时间的强度。我们将使用标准的细胞生物学、生物化学和分子生物学技术来表征生物对实验条件的反应。这些目标将使我们能够解决阻断一氧化氮是否是在金黄色葡萄球菌蜂窝织炎期间加强细菌清除的治疗选择。这一EDRG建议位于免疫学和功能淋巴生物学的十字路口，到目前为止，这一交叉路口一直未得到充分研究。本文提出的工作将通过应用淋巴功能原理来研究金黄色葡萄球菌皮肤感染这一重要的公共卫生问题，从而推动这一领域的发展。