权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of dendritic cells by estrogen receptors during influenza infection

流感感染期间雌激素受体对树突状细胞的调节

基本信息

批准号：
8197771
负责人：
Susan Kovats
金额：
$ 20.38万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197771
关键词：
Accounting Address Adjuvant Adult Affect Antigen Presentation Antiviral Response Biology Bone Marrow Cells Competence Cytokine Activation Data Dendritic Cells Development Endocrine Environment Environmental Risk Factor Equilibrium Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogens Exhibits Female Gonadal Steroid Hormones Granulocyte-Macrophage Colony-Stimulating Factor Hormone Receptor Human ITGAM gene ITGAX gene Immune Immune response Immune system Immunization Infection Inflammatory Influenza Influenza A Virus, H1N1 Subtype Interferon Regulatory Factor 4 Interferon Type I Knowledge Lead Ligands Lung Mediastinal lymph node group Mediating Modeling Molecular Morbidity - disease rate Mus Myelogenous Organ Outcome Pathway interactions Physiological Population Predisposition Prevalence Process Production Receptor Signaling Regulation Relative (related person)Rodent Rodent Model Severities Sex Bias Sex Characteristics Signal Transduction Testing Tissues Toll-like receptors Variant Virus Virus Diseases Woman Work abstracting cell mediated immune response cytokine in vivo influenzavirus innovation insight lymph nodes male men monocyte mortality novel pandemic disease progenitor public health relevance response sex transcription factor

项目摘要

DESCRIPTION (provided by applicant): Regulation of dendritic cells by estrogen receptors during influenza infection Abstract Influenza virus infections result in significant morbidity and mortality in the human population, and the recent H1N1 pandemic underscores the need to understand the physiological and environmental risk factors that regulate the human variation in immune responses to influenza virus. This project will determine how one such physiological factor, estrogen receptor alpha (ER1) signaling, regulates the innate immune response to influenza virus infection in mice. Although humans and rodents often exhibit marked sex differences in the prevalence and severity of infection, little is known about the molecular mechanisms by which these sex differences occur and if they are mediated through effects of sex hormones on the innate immune responses elaborated by monocytes and dendritic cells (DC). The functional importance of newly developed populations of inflammatory and tissue DC in the lung and mediastinal lymph nodes during murine influenza infection has recently been elucidated. We have shown that estradiol/ER1 signaling promotes the GM-CSF-driven inflammatory pathway that leads to development of CD11b+ DC. These DC have features of the tissue and inflammatory DC that are crucial during influenza infection. Our data also show that ER1 signaling modulates the activation and function of mature DC. In this project, we will test the hypothesis that during influenza infection, the de novo development and function of DC are regulated by ER1 signaling in response to normal endogenous levels of estrogens. We will evaluate two distinct mechanisms by which ER1 signaling might influence DC-mediated immune responses during infection in vivo: (1) regulation of de novo DC development from inflammatory monocytes or other DC precursors, and (2) regulation of the functional responses of mature DC. We will address these questions using innovative models that include competitive ER1+/ER1-/- bone marrow chimeric mice and mice in which ER1 deficiency is restricted to DC. These novel models will lead to new insights into how ER1 signaling in response to physiological levels of endogenous estrogens regulates de novo DC development and functional responses during influenza virus infection in both sexes. PUBLIC HEALTH RELEVANCE: Cells of the human and murine immune systems are capable of responding to natural estrogens. We seek to understand how estrogens control the development and function of key regulatory cells of the immune system, termed dendritic cells, during influenza virus infection. This knowledge will determine how natural estrogen levels regulate the immune response during influenza infection and help elucidate why men and women differ in susceptibility to viral infections.

描述（由申请人提供）：在流感感染期间雌激素受体对树突状细胞的调节摘要流感病毒感染导致人群中显著的发病率和死亡率，并且最近的H1N1大流行强调了理解调节人类对流感病毒的免疫应答变化的生理和环境风险因素的需要。该项目将确定一个这样的生理因素，雌激素受体α（ER 1）信号传导，如何调节小鼠对流感病毒感染的先天免疫反应。虽然人类和啮齿类动物经常表现出显着的性别差异的感染的患病率和严重程度，很少有人知道这些性别差异发生的分子机制，如果他们介导的先天免疫反应的单核细胞和树突状细胞（DC）的性激素的影响。最近已经阐明了在鼠流感感染期间肺和纵隔淋巴结中新开发的炎性和组织DC群体的功能重要性。我们已经证明，雌二醇/ER 1信号促进GM-CSF驱动的炎症通路，导致CD 11b + DC的发展。这些DC具有在流感感染期间至关重要的组织和炎性DC的特征。我们的数据还表明，ER 1信号调节成熟DC的激活和功能。在这个项目中，我们将测试的假设，在流感感染期间，从头发展和功能的DC调节ER 1信号在响应正常的内源性雌激素水平。我们将评估两种不同的机制，其中ER 1信号可能会影响DC介导的免疫反应在体内感染过程中：（1）调节从头DC发展的炎症单核细胞或其他DC前体，和（2）调节成熟DC的功能反应。我们将使用包括竞争性ER 1 +/ER 1-/-骨髓嵌合小鼠和ER 1缺陷仅限于DC的小鼠的创新模型来解决这些问题。这些新的模型将导致新的见解如何ER 1信号在响应生理水平的内源性雌激素调节从头DC的发展和功能反应在两性流感病毒感染。公共卫生相关性：人类和小鼠免疫系统的细胞能够对天然雌激素做出反应。我们试图了解在流感病毒感染期间雌激素如何控制免疫系统的关键调节细胞（称为树突状细胞）的发育和功能。这些知识将确定天然雌激素水平如何调节流感感染期间的免疫反应，并有助于阐明为什么男性和女性对病毒感染的易感性不同。