FDRC1 and Follicular Dendritic Cell Signaling Pathways

FDRC1 和滤泡树突状细胞信号通路

• 批准号: 7559280
• 负责人: Edward A Clark
• 金额: $ 43.47万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559280
• 关键词: Affect; Aftercare; Albers-Schonberg disease; Antigens; Apoptosis; Autoimmune Diseases; Binding; Blood Vessels; Bone Diseases; C-Type Lectins; Caspase; Cell Death; Cell Maturation; Cell Survival; Cell physiology; Cells; Chronic; Communicable Diseases; Communication; Coronary Arteriosclerosis; Cytomegalovirus; Data; Defect; Delayed Hypersensitivity; Dendritic Cells; Development; Disease; Encephalomyelitis; Endotoxemia; Estradiol; Estrogens; Experimental Autoimmune Encephalomyelitis; Family; Follicular Dendritic Cells; Homeostasis; Human; Immune System Diseases; Immune response; Immune system; Immunity; Immunologist; In Vitro; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Lead; Life; Ligands; Lipopolysaccharides; Longevity; Lymphoid; Measles virus; Mediating; Multiple Sclerosis; Mus; Mutation; Osteoporosis; Pathway interactions; Patients; Pattern recognition receptor; Peptides; Peripheral; Play; Process; Production; Proteins; Regulation; Research Personnel; Resistance; Rheumatoid Arthritis; Risk; Role; Sentinel; Serum; Severities; Signal Pathway; Signal Transduction; Site; System; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; TNFRSF5 gene; TRANCE protein; Testing; Toll-like receptors; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumor necrosis factor receptor 11b; Virus; Woman; autoimmune lymphoproliferative syndrome; bone metabolism; calcification; caspase-10; cell motility; chemokine receptor; cytokine; human TNFRSF1A protein; immunoregulation; in vitro testing; in vivo; insight; interest; killings; lymph nodes; member; men; overexpression; pathogen; programs; promoter; receptor; response; tumor necrosis factor alpha receptor

Dendritic cells (DCs) help to coordinate and bridge innate and adaptive immune responses. DCs for the most part are short lived; how long they live and where may influence whether they induce immunity, tolerance or autoimmune disease. DC fate and cytokine production are regulated in part by RANK (receptor activator ofNF-IcB ligand), receptors for TRAIL (tumor necrosis factor-alpha-related papooses-inducing ligand) and the soluble 'decoy' receptor osteoprotegerin (OPG), which binds RANK ligand (RANKL) and TRAIL. Our data suggest that DC cytokine production and survival are dysregulated in the absence of OPG. We plan to define the role the RANKL/RANK/OPG system plays in regulating DCs. We wiU test the hypothesis that OPG regulates dendritic cell survival by modulating the RANKL/RANK and TRAIL/TRAIL receptor pathways. We will test whether OPG -/- or RANK -/- DCs differ from wildtype DCs in their survival in vitro or in vivo. The effect of overexpressing the survival protein Bcl-2 on the DC- restricted CD1 lc promoter will be evaluated in OPG -/- and RANK -/- mice. We predict that by altering the lifespan of DCs in vivo, that underlying defects in disease, bone homeostasis and peripheral lymphoid development will be altered. We will also test the hypothesis that human immature DCs (iDCs) and mature DCs (mDCs) differ in how they are regulated by the RANK/OPG/TRAIL receptor pathways and by caspases. Next we will test the hypothesis that OPG regulates the profile and levels of cytoldnes produced by DC subsets. We will define how the absence of OPG or RANK affects cytokine production in vitro and test whether the cytokine dysregulation in OPG -/- and RANK -/- mice influences in vivo responses to lipopolysaccharide (LPS) and peptide-induced experimental autoimmune encephalomyelitis (EAE). The expression of OPG, RANKL and TRAIL receptors is regulated by 17-13-estradiol (E2). Therefore, we will test the hypotheses that E2 modulates peptide-induced EAE, DC survival and cytokine production via an OPG-<lependent pathway. If OPG is required for E2 to downregulate EAE, we will explore if this is due in part to direct effects of E2 on DCs. Further understanding of how DC longevity and cytokine secretion are regulated may lead to new insights into the causes of and treatments for chronic immunologic diseases like rheumatoid arthritis and multiple sclerosis. The proposed studies may also contribute to understanding of how E2 and OPG contribute to the development of inflammatory immune responses.

树突状细胞（DC）有助于协调和桥接先天性和适应性免疫反应。大多数DC是 寿命短;它们的寿命有多长以及在哪里可能影响它们是否诱导免疫、耐受或自身免疫 疾病DC命运和细胞因子产生部分受RANK（NF-IcB配体的受体激活剂）、受体 TRAIL（肿瘤坏死因子-α相关的木瓜蛋白酶诱导配体）和可溶性“诱饵”受体 骨保护素（OPG），其结合RANK配体（RANKL）和TRAIL。我们的数据表明DC细胞因子 在没有OPG的情况下，产生和存活失调。我们计划定义RANKL/RANK/OPG的角色 制度在规范发展中国家方面的作用。我们将检验OPG通过调节树突状细胞的存活来调节树突状细胞存活的假设。 RANKL/RANK和TRAIL/TRAIL受体途径。我们将测试OPG -/-或RANK -/-DC是否与 野生型DC在体外或体内的存活率。过度表达存活蛋白Bcl-2对DC-2表达的影响 将在OPG -/-和RANK -/-小鼠中评估限制性CD 11 c启动子。我们预测通过改变 在体内，DCs在疾病、骨稳态和外周淋巴发育中的潜在缺陷将被改变。 我们还将测试人类未成熟DC（iDC）和成熟DC（mDC）在它们如何被激活方面不同的假设。 受RANK/OPG/TRAIL受体途径和半胱天冬酶调节。接下来，我们将测试OPG 调节DC亚群产生的cytolnes的分布和水平。我们将定义OPG或 RANK影响体外细胞因子的产生，并测试OPG -/-和RANK -/-小鼠中细胞因子的失调是否 影响体内对脂多糖（LPS）和肽诱导的实验性自身免疫反应 脑脊髓炎（EAE）。OPG、RANKL和TRAIL受体的表达受17-13-雌二醇（E2）调节。 因此，我们将检验E2调节肽诱导的EAE、DC存活和细胞因子产生的假设 通过OPG依赖性途径。如果OPG是E2下调EAE所必需的，我们将探讨这是否部分是由于 E2对DCs的直接作用。进一步了解DC寿命和细胞因子分泌是如何调节的， 对慢性免疫性疾病（如类风湿性关节炎）的病因和治疗方法有了新的认识， 多发性硬化拟议的研究也可能有助于了解E2和OPG如何促进 炎症免疫反应的发展。