FDRC1 AND FOLLICULAR DENDRITIC CELL SIGNALING PATHWAYS

描述（由申请人提供）：树突状细胞（dc）有助于协调和桥接先天和适应性免疫反应。dc在大多数情况下都是短暂的；它们存活的时间和地点可能会影响它们是否诱导免疫、耐受性或自身免疫性疾病。DC命运和细胞因子的产生在一定程度上受RANK （NF-kappaB配体的受体激活剂）、TRAIL（肿瘤坏死因子- α相关的papose诱导配体）受体和可溶性“诱饵”受体骨保护素（OPG）的调节，后者结合RANK配体（RANKL）和TRAIL。我们的数据表明，在没有OPG的情况下，DC细胞因子的产生和存活是失调的。我们计划确定RANKL/RANK/OPG系统在调节dc中的作用。我们将验证OPG通过调节RANKL/RANK和TRAIL/TRAIL受体通路调节树突状细胞存活的假设。我们将测试OPG -/-或RANK -/- dc在体外或体内的存活是否与野生型dc不同。过表达存活蛋白Bcl-2对Dc限制性CD11c启动子的影响将在OPG -/-和RANK -/-小鼠中进行评估。我们预测，通过改变dc在体内的寿命，疾病、骨稳态和外周淋巴细胞发育的潜在缺陷将被改变。我们还将验证人类未成熟dc （idc）和成熟dc （mdc）在受ANK/OPG/TRAIL受体途径和半胱天酶调节的方式上的差异。接下来，我们将验证OPG调节DC亚群产生的细胞因子的特征和水平的假设。我们将在体外确定OPG或RANK缺失如何影响细胞因子的产生，并测试OPG -/-和RANK -/-小鼠的细胞因子失调是否会影响体内对脂多糖（LPS）和肽诱导的实验性自身免疫性脑脊髓炎（EAE）的反应。OPG、RANKL和TRAIL受体的表达受17- β -雌二醇（E2）的调控。因此，我们将验证E2通过opg依赖性途径调节肽诱导的EAE、DC存活和细胞因子产生的假设。如果E2下调EAE需要OPG，我们将探讨这是否部分归因于E2对DCs的直接影响。进一步了解DC寿命和细胞因子分泌是如何被调节的，可能会为类风湿关节炎和多发性硬化症等慢性免疫性疾病的病因和治疗提供新的见解。拟议的研究也可能有助于理解E2和OPG如何促进炎症免疫反应的发展。

DESCRIPTION (provided by applicant): 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 of NF-kappaB 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 will 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 wild type DCs in their survival in vitro or in vivo. The effect of overexpressing the survival protein Bcl-2 on the Dc restricted CD11c 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 ANK/OPG/TRAIL receptor pathways and by caspases. Next we will test the hypothesis that OPG regulates the profile and levels of cytokines 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-beta-estradiol (E2). Therefore, we will test the hypotheses that E2 modulates peptide-induced EAE, DC survival and cytokine production via an OPG-dependent 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.