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）：探索性开发研究赠款的总体目标是研究细菌感染是否抑制淋巴功能并因此抑制免疫反应。这将为管理难以解决的感染的新方法提供最初的见解，其中许多目前需要静脉注射抗生素治疗，这可能导致抗生素抗生素抗生素菌株 - 另一个重大问题。 PI是淋巴研究专家，尤其是使用新型插入式成像技术和动物模型的功能研究。他召集了一支由一级氧化物生物学专家Dai Fukumura博士组成的一流团队，Nancy H. Ruddle博士是免疫生物学，Cytokines和Autommune疾病专家Nancy H. Ruddle，S）和S的专家Jean C. Lee博士。金黄色的生物学和疫苗开发。这个健壮且经验丰富的研究团队，以及埃德温·斯蒂尔（Edwin L. Steele）实验室，马萨诸塞州综合医院和哈佛医学院的资源，确保了该EDRG提出的创新研究的最佳环境。初始淋巴血管采用间质液，从而产生通过收集淋巴管和淋巴结进行运输的淋巴，并最终恢复血液循环以维持组织液平衡。抗原和抗原呈递细胞（APC）使用此途径进入排水淋巴结（LN）并启动免疫反应。慢性感染，例如蜂窝织炎，通常与淋巴水肿有关，这通常与收集淋巴血管的功能发生故障或破坏有关。在美国，蜂窝织炎病例每年造成近40万次住院。在这项探索性发展研究赠款建议中，我们将检验以下假设：这些难以解决的感染是通过损害排干感染区域的淋巴管自主收缩的损害，从而将淋巴结的信号限制在感染部位的淋巴结和引起毒素积累。我们将使用新型的鼠模型，该模型允许自主淋巴收缩成像并在室内进行量化。我们将研究s期间淋巴功能的损害。金黄色的感染（AIM 1），宿主从髓样衍生的抑制细胞引起淋巴损伤（AIM 2）和S产生的一氧化氮的作用的宿主衍生氧化物的作用。金黄色一氧化氮合酶在淋巴功能上（AIM 3）。为了实现这些目标，我们将衡量淋巴收缩，淋巴流，抗原转运和感染持续时间的强度。我们将使用标准细胞生物学，生物化学和分子生物学技术来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封闭一氧化氮是否是增强s过程中细菌清除率的治疗选择。金黄色葡萄球炎。该EDRG的建议在于免疫学和功能性淋巴生物学之间的十字路口，该交集迄今已被研究过。这里提出的工作将通过应用淋巴功能的原理来研究S的重要公共卫生问题。金黄色皮肤感染。