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）：本探索性发展研究资助的总体目标是研究细菌感染是否会抑制淋巴功能，从而抑制免疫反应。这将为管理难以解决的感染的新方法提供初步见解，目前许多感染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是淋巴研究方面的专家，特别是使用新的活体成像技术和动物模型进行功能研究。他组建了一个由一氧化氮生物学专家Dai Fukumura博士、免疫生物学、细胞因子和自身免疫性疾病专家Nancy H. Ruddle博士和金黄色葡萄球菌生物学和疫苗开发专家Jean C. Lee博士组成的一流团队。这个强大而经验丰富的研究团队，以及Edwin L. Steele实验室、马萨诸塞州总医院和哈佛医学院的可用资源，确保了本EDRG中提出的创新研究的最佳环境。最初的淋巴管吸收间质液产生淋巴，淋巴通过集合淋巴管和淋巴结运输，最终返回血液循环，维持组织液平衡。抗原和抗原提呈细胞（APC）通过这一途径进入引流淋巴结（LN）并启动免疫反应。慢性感染，如蜂窝织炎，通常与淋巴水肿有关，而淋巴水肿通常与淋巴管收集功能的功能障碍或破坏有关。在美国，蜂窝织炎每年导致近40万人住院。在这一探索性发展研究拨款提案中，我们将验证这样一种假设，即这些难以解决的感染是由于引流感染区域的淋巴管自主收缩受损，从而限制了向淋巴结的信号传递，并导致感染部位的毒素积聚。我们将使用我们的新小鼠模型，该模型允许自主淋巴收缩在体内成像和量化。我们将研究金黄色葡萄球菌感染期间淋巴功能的损害（目的1），来自骨髓源抑制细胞的宿主来源的一氧化氮在引起淋巴功能损害中的作用（目的2），以及金黄色葡萄球菌一氧化氮合酶产生的一氧化氮在淋巴功能中的作用（目的3）。为了达到这些目的，我们将测量淋巴收缩的强度、淋巴流量、抗原运输和感染的持续时间。我们将使用标准细胞生物学、生物化学和分子生物学技术来描述对实验条件的生物反应。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，以提高金黄色葡萄球菌蜂窝织炎期间细菌的清除。这个EDRG提案位于免疫学和功能性淋巴生物学之间的十字路口，这是一个迄今为止尚未得到充分研究的交叉点。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的重要公共卫生问题，从而推动这一领域的发展。