FDRC1 and Follicular Dendritic Cell Signaling Pathways

FDRC1 和滤泡树突状细胞信号通路

• 批准号: 8288880
• 负责人: Edward A Clark
• 金额: $ 45.37万
• 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/8288880
• 关键词: Affect; Aftercare; Albers-Schonberg disease; Antigen-Presenting Cells; 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; 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; TNFSF10 gene; TRANCE protein; Testing; Toll-like receptors; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor necrosis factor receptor 11b; Virus; Woman; autoimmune lymphoproliferative syndrome; bone metabolism; calcification; caspase-10; cell motility; chemokine receptor; cytokine; immunoregulation; in vitro testing; in vivo; insight; interest; killings; lymph nodes; member; men; overexpression; pathogen; programs; promoter; receptor; response

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免疫和获得性免疫反应。大部分分布式控制系统是 短命；它们的寿命有多长以及在哪里可能会影响它们是否诱导免疫、耐受或自身免疫 疾病。DC的命运和细胞因子的产生在一定程度上受RANK(核因子-ICB配体受体激活剂)、受体的调节 TRAIL(肿瘤坏死因子-α相关乳头病诱导配体)和可溶性‘诱饵’受体 骨保护素(OPG)，结合RANKL和TRAIL。我们的数据表明DC细胞因子 在没有OPG的情况下，生产和生存受到失调。我们计划定义RANKL/RANK/OPG的角色 制度在规范DC方面发挥了作用。我们对OPG通过调控树突状细胞存活的假设进行了验证 RANKL/RANK和TRAIL/TRAIL受体通路。我们将测试OPG-/-或职级-/-区议会是否与 野生型DC在体外和体内存活的情况。过表达存活蛋白Bc l-2对DC-2的影响 限制性CD1lc启动子将在OPG-/-和RANK-/-小鼠中进行评估。我们预测，通过改变生命周期， 在体内，疾病、骨稳态和外周淋巴样发育方面的潜在缺陷将发生改变。 我们还将测试人类未成熟DC(IDCs)和成熟DC(MDCs)如何不同的假设 受RANK/OPG/TRAIL受体通路和半胱氨酸蛋白酶的调节。接下来我们将检验OPG的假设 调节DC亚群产生的细胞毒性的分布和水平。我们将定义没有OPG或 RANK影响体外细胞因子的产生并检测OPG-/-和RANK-/-小鼠细胞因子是否失调 脂多糖和多肽诱导的实验性自身免疫对体内反应的影响 脑脊髓炎(EAE)。OPG、RANKL和TRAIL受体的表达受17-13-雌二醇(E2)的调节。 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-&lt；一条下垂的通道。如果E2需要OPG来下调EAE，我们将探讨这是否部分是由于 雌二醇对DC的直接作用。进一步了解DC的寿命和细胞因子分泌是如何调节的可能会导致 对慢性免疫性疾病的病因和治疗有新的见解，如类风湿性关节炎和 多发性硬化症。拟议的研究也可能有助于理解E2和OPG是如何促进 炎性免疫反应的发展。