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

Intracellular Receptors and Gonococcal Induction of Proinflammatory

细胞内受体和淋球菌促炎诱导

基本信息

批准号：
8525327
负责人：
Caroline A Genco
金额：
$ 37.23万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8525327
关键词：
Animals Antibodies Automobile Driving Binding Bone Marrow Breeding Cell physiology Cells Cytokine Activation Disease Embryo Epithelial Cells Genital system Human Immune Immune response Immunologic Receptors In Vitro Infection Inflammation Inflammatory Inflammatory Response Interleukin-6 Interleukins Kidney Knockout Mice Knowledge Laboratories Life Ligands Mammalian Oviducts Mediating Mediator of activation protein Modeling Mus Natural Immunity Neisseria Neisseria gonorrhoeae Nucleotides Pathology Pattern recognition receptor Phagocytes Production Proteins Receptor Signaling Receptor-Interacting Serine/Threonine Protein Kinase 2 Role Sexually Transmitted Diseases Signal Transduction System TLR2 gene TLR4 gene Testing Toll-like receptors Tumor Necrosis Factor-alpha adaptive immunity base chemokine cytokine improved in vivo inhibitor-of-apoptosis protein macrophage mouse model novel pathogen receptor reproductive response

项目摘要

Proinflammatory cytokines are expressed in vivo during infection with the sexually transmitted disease pathogen Neisseria gonorrhoeae and contribute to disease pathology. The activation of proinflammatory cytokines is directed by pattern recognition receptors (PRRs). PRRs can be classified as transmembrane molecules such at the Toll-like receptors (TLRs), or cytosolic molecules including Nod- like receptors (NLRs). TLR2 and TLR4 function as receptors for Neisseria ligands. However, nothing is known about cytosolic molecules that respond to intracellular N. gonorrhoeae. We recently demonstrated that blocking signaling through TLRs using antagonistic antibodies only partially reduced the production of proinflammatory cytokines following N. gonorrhoeae infection of epithelial cells suggesting that intracellular NLRs may be employed for N. gonorrhoeae induced proinflammatory cytokines. We also demonstrated that infection of epithelial cells with N. gonorrhoeae induced the expression of NLRs including Nodi and a protein recently implicated in intracellular immune recognition, inhibitor of apoptosis protein (clAP-2), as well as the receptor interacting serine-threonine kinase 2 (R1P2), a key mediator of innate immune signaling. Furthermore, we established that N. gonorrhoeae stimulates proinflammatory cytokine responses through Nod1 and Nod 2 in an over expression system. Based on these observations we propose that N. gonorrhoeae employs specific intracellular signaling receptors that respond to intracellular gonococci and or their ligands, resulting in proinflammatory responses that contribute to N. gonorrhoeae induced inflammation in vivo. To test this hypothesis we propose the following aims: 1. To define the role of NLR signaling receptors (clAP2, N0D1, and N0D2) in N. gonorrhoeae induction of proinflammatory cytokines in human epithelial cells and macrophages; 2. To define the role of NLR signaling receptors (clAP2, N0D1, and N0D2) in N. gonorrhoeae induction of proinflammatory cytokines in murine epithelial cells and macrophages; and 3. To define the role of NLRs in N. gonorrhoeae induced inflammatory responses in a mouse model.

促炎细胞因子在性传播疾病病原体淋病奈瑟菌感染期间在体内表达，并促进疾病病理学。促炎细胞因子的激活由模式识别受体（PRR）指导。PRR可以被分类为跨膜分子，例如Toll样受体（TLR），或包括Nod样受体（NLR）的胞质分子。TLR 2和TLR 4作为奈瑟氏菌配体的受体发挥功能。然而，对胞内N应答的胞质分子却一无所知。淋病我们最近证实，使用拮抗性抗体阻断通过TLR的信号传导只能部分减少N。淋病感染的上皮细胞，表明细胞内NLR可用于N.淋病诱导的促炎细胞因子。我们还证实了用N.淋病诱导NLR的表达，包括Nodi和最近与细胞内免疫识别有关的蛋白质、凋亡蛋白抑制剂（cIAP-2）以及受体相互作用丝氨酸-苏氨酸激酶2（R1 P2），其是先天免疫信号传导的关键介体。此外，我们还证明了N.淋病通过过表达系统中的Nod 1和Nod 2刺激促炎细胞因子应答。基于这些观察，我们提出N.淋病使用特异性细胞内信号受体，其响应细胞内淋球菌和/或其配体，导致促炎性反应，从而导致N.淋病在体内引起炎症。为了验证这一假设，我们提出了以下目标：1。确定NLR信号受体（cIAP 2、N 0 D1和N 0 D2）在N.淋病诱导人上皮细胞和巨噬细胞中的促炎细胞因子; 2.为了明确NLR信号受体（cIAP 2、N 0 D1和N 0 D2）在N.淋病诱导鼠上皮细胞和巨噬细胞中的促炎细胞因子;和3.明确NLR在N.淋病在小鼠模型中诱导炎症反应。