Fc gamma RIIB and Inflammation-Related Vascular Disease

描述（由申请人提供）：Fc受体（FcR）经典地调节免疫系统中B细胞和其他效应细胞对IgG的反应。我们发现抑制FcR， Fc？RIIB在内皮中含量丰富，可介导内皮NO合成酶（eNOS）被IgG、c -反应蛋白（CRP）和血清淀粉样蛋白P组分（SAP）拮抗，在小鼠体内相当于CRP。eNOS的拮抗作用是通过抑制Akt和eNOS激活磷酸化而发生的。由于在小鼠内皮细胞中Akt和eNOS激活磷酸化与肥胖诱导的高血压（HTN）的关联类似地减弱，全球Fc？RIIB-/-小鼠被置于高脂肪饮食（HFD）中，发现尽管体重增加与Fc？RIIB+/+， null小鼠免受肥胖诱导的HTN。该提案的总体目标是确定Fc？RIIB参与肥胖诱导HTN的发病机制。目的1是确定内皮细胞Fc？RIIB参与了这种障碍。利用无线遥测技术，将野生型小鼠与内皮细胞特异性Fc？RIIB缺失对正常鼠粮和HFD的影响。hfd诱导的血管Akt和eNOS磷酸化状态的变化将在这些组中进行评估，HTN的潜在保护作用将在内皮中选择性表达构成型活性Akt的小鼠中进行评估。一个anti-Fc吗?RIIB阻断抗体将用于确定针对受体的干预是否能阻止HTN。目标2是识别Fc？RIIB配体介导肥胖诱导的HTN。我们发现，高脂饲料小鼠的SAP增加，从高脂饲料小鼠中分离的IgG能有效拮抗培养内皮中的eNOS，而正常饲料小鼠的IgG则不能。因此，hfd诱导的HTN将在缺乏B细胞和IgG的野生型小鼠与SAP-/-和免疫球蛋白u重链缺失小鼠中进行研究。如果这项工作涉及到IgG，一种B细胞消耗抗体和一种fcrn导向的增强IgG降解的药物将被用来确定降低Fc？RIIB配体丰度可预防肥胖诱导的HTN。目标3是确定Fc？RIIB影响戊烷素水平升高或肥胖的人HTN的发展。常见单核苷酸多态性（SNP）与Fc？RIIB和事件HTN将在妇女基因组健康研究中进行评估，这是一项超过25,000名妇女的前瞻性队列研究。推动力包括发现Fc？达拉斯心脏研究中不能拮抗eNOS的RIIB变异体及CRP水平为2.0mg/L受试者的初步调查在非裔美国人中，基因型频率提供了足够的统计力量，功能丧失变体与较低的收缩压有关。通过实现这些目标，这个新颖的概念将得到检验。内皮和FcR配体中的RIIB参与HTN的发病机制。针对HTN的独特预防或治疗措施可能会随之而来，HTN会使肥胖和其他慢性炎症状况复杂化。

DESCRIPTION (provided by applicant): Fc receptors (FcR) classically modulate responses to IgG in B cells and other effector cells in the immune system. We discovered that the inhibitory FcR, Fc?RIIB, is abundant in endothelium, and that it mediates endothelial NO synthase (eNOS) antagonism by IgG, C-reactive protein (CRP) and serum amyloid P component (SAP), which is the CRP-equivalent in mice. The eNOS antagonism occurs via inhibition of Akt and eNOS activating phosphorylation. Since in mice endothelial Akt and eNOS activating phosphorylation are similarly attenuated in association with obesity-induced hypertension (HTN), global Fc?RIIB-/- mice were placed on high-fat diet (HFD) and it was discovered that despite weight gain equal to that of Fc?RIIB+/+, the null mice are protected from obesity-induced HTN. The OVERALL GOAL of the proposal is to determine how Fc?RIIB contributes to the pathogenesis of obesity-induced HTN. Aim 1 is to determine how endothelial cell Fc?RIIB participates in the disorder. Using radiotelemetry, BP will be compared in wild-type mice vs. mice with endothelial cell-specific Fc?RIIB deletion on normal chow vs. HFD. HFD-induced changes in vascular Akt and eNOS phosphorylation state will be evaluated in these groups, and potential protection from the HTN will be assessed in mice expressing constitutively-active Akt selectively in endothelium. An anti-Fc?RIIB blocking antibody will be used to determine if an intervention targeting the receptor prevents the HTN. Aim 2 is to identity the Fc?RIIB ligand(s) mediating obesity-induced HTN. We've discovered that SAP increases in mice on HFD, and that IgG isolated from HFD-fed mice potently antagonizes eNOS in cultured endothelium, whereas IgG from normal chow-fed mice does not. HFD-induced HTN will therefore be studied in wild-type vs. SAP-/- and immunoglobulin u heavy-chain null mice deficient in B cells and IgG. If this work implicates IgG, a B cell depleting antibody and an FcRn-directed agent that enhances IgG degradation will be used to determine if interventions that decrease Fc?RIIB ligand abundance prevent obesity-induced HTN. Aim 3 is to determine how Fc?RIIB influences the development of HTN in humans with elevated pentraxin levels or obesity. The association between common single nucleotide polymorphisms (SNP) in Fc?RIIB and incident HTN will be evaluated in the Women's Genome Health Study, which is a prospective cohort study of over 25,000 women. Impetus includes the discovery of an Fc?RIIB variant incapable of eNOS antagonism and a preliminary query of subjects with CRP>2.0mg/L in the Dallas Heart Study; in African Americans in whom genotype frequency provided sufficient statistical power, the loss-of-function variant was associated with lower systolic BP. By accomplishing these aims, the novel concept will be tested that Fc?RIIB in endothelium and FcR ligands participate in the pathogenesis of HTN. Unique preventative or treatment measures to combat the HTN that complicates obesity and other chronic inflammatory conditions will potentially follow.