Characterization of lymphatic contraction during infection

感染期间淋巴收缩的特征

• 批准号: 8225628
• 负责人: TIMOTHY P PADERA
• 金额: $ 26.2万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225628
• 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; 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. PUBLIC HEALTH RELEVANCE: Chronic skin infections are responsible for over 400,000 hospital admissions in the US each year, many of which require intravenous antibiotic treatment that can ultimately lead to the formation of antibiotic resistant bacteria. Here will study whether nitric oxide produced by either the host or bacteria during infections impairs lymphatic function and thus limits the immune response. We can then use these data to study potential nitric oxide based interventions for the treatment of chronic skin infections, thereby limiting the need for further antibiotics.

描述（由申请人提供）：这项探索性发展研究资助的总体目标是调查细菌感染是否抑制淋巴功能，从而抑制免疫反应。这将为管理难以解决的感染提供初步的见解，其中许多感染目前需要静脉注射抗生素治疗，这可能导致抗生素耐药菌株-另一个重大问题。PI是淋巴研究方面的专家，特别是使用新型活体成像技术和动物模型进行功能研究。他组建了一个一流的团队，包括一氧化氮生物学专家大井村博士，免疫生物学、细胞因子和自身免疫性疾病方面的专家Ruddle和JeanC.李，一个专家在s。金黄色葡萄球菌生物学和疫苗开发。这个强大而经验丰富的研究团队，沿着在埃德温L。Steele实验室、马萨诸塞州总医院和哈佛医学院确保为本EDRG中提出的创新研究提供最佳环境。最初的淋巴管吸收间质液以产生淋巴，淋巴通过集合淋巴管和淋巴结运输，并最终返回血液循环以维持组织液平衡。抗原和抗原呈递细胞（APC）使用该途径进入引流淋巴结（LN）并启动免疫应答。慢性感染，如蜂窝织炎，经常与水肿，这是一般与功能障碍或收集淋巴管的功能中断。蜂窝织炎的病例在美国每年造成近40万例住院。在这项探索性发展研究资助计划中，我们将测试以下假设：这些难以解决的感染是由引流感染区域的淋巴管自主收缩受损所帮助的，从而限制了淋巴结的信号传导并导致感染部位的毒素积累。我们将使用我们的新的小鼠模型，允许自主淋巴收缩进行成像和定量体内。我们将研究s期间淋巴功能的损害。金黄色葡萄球菌感染（Aim 1），来自骨髓来源的抑制细胞的宿主来源的一氧化氮在引起淋巴损伤中的作用（Aim 2）和由S.金黄色葡萄球菌一氧化氮合酶对淋巴功能的影响（目的3）。为了实现这些目标，我们将测量淋巴收缩的强度、淋巴流量、抗原转运和感染持续时间。我们将使用标准细胞生物学、生物化学和分子生物学技术表征对实验条件的生物学反应。这些目标将使我们能够解决阻断一氧化氮是否是一种治疗选择，以提高细菌的清除率。金黄色蜂窝织炎。这个EDRG建议位于免疫学和功能性淋巴生物学之间的十字路口，迄今为止尚未充分研究。这里提出的工作将通过应用淋巴功能的原理来研究美国重要的公共卫生问题来推动这一领域。金黄色皮肤感染。 公共卫生关系：在美国，慢性皮肤感染每年导致超过40万人住院，其中许多人需要静脉注射抗生素治疗，最终可能导致抗生素耐药性细菌的形成。这里将研究在感染过程中宿主或细菌产生的一氧化氮是否会损害淋巴功能，从而限制免疫反应。然后，我们可以使用这些数据来研究潜在的基于一氧化氮的干预措施，用于治疗慢性皮肤感染，从而限制对进一步抗生素的需求。