Fc gamma RIIB and Inflammation-Related Vascular Disease

Fc gamma RIIB 和炎症相关血管疾病

• 批准号: 8502166
• 负责人: PHILIP W SHAUL
• 金额: $ 35.63万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-16 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502166
• 关键词: Address; African American; Agonist; Alleles; Antibodies; Antihypertensive Agents; Attenuated; B-Lymphocytes; Binding; Blocking Antibodies; Blood Vessels; C-reactive protein; Cardiovascular system; Cell Line; Cell Surface Receptors; Chronic; Cohort Studies; Development; Diet; Disease; Effector Cell; Endothelial Cells; Endothelium; Ethnic group; Fatty acid glycerol esters; Fc Receptor; Fc gamma receptor IIB; Frequencies; Future; Genes; Genetic; Genome; Genotype; Health; Heart; Hispanics; Human; Hypertension; Immune system; Immunoglobulin G; Immunoglobulins; Inflammation; Inflammatory; Inflammatory Response; Intervention; Knockout Mice; Knowledge; Lead; Leukocytes; Ligands; Measures; Mediating; Mediator of activation protein; Mus; Nitric Oxide Synthase; Obese Mice; Obesity; Obesity Related Hypertension; Pathogenesis; Phosphorylation; Phosphotransferases; Play; Process; Production; Reporting; Research; Risk; Role; Sampling; Serum; Serum Amyloid P-Component; Signal Transduction; Single Nucleotide Polymorphism; Study of serum; Testing; Therapeutic; Variant; Vascular Diseases; Weight Gain; Wild Type Mouse; Woman; Work; attenuation; base; cadherin 5; cohort; combat; feeding; genetic variant; human FCGR2B protein; loss of function; mouse model; neonatal Fc receptor; novel; population based; prevent; programs; promoter; prospective; public health relevance; racial and ethnic; receptor; response; translational approach; trend

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.

描述（由申请人提供）：FC受体（FCR）经典地调节了免疫系统中B细胞和其他效应细胞中对IgG的反应。我们发现抑制性FCR Fc？riIB在内皮中含量丰富，并且它通过IgG，C反应蛋白（CRP）和血清淀粉样蛋白P成分（SAP）介导了内皮NO合酶（ENOS）拮抗作用，这是小鼠中CRP等量的。 eNOS拮抗作用是通过抑制AKT和ENOS激活磷酸化的。由于在小鼠内皮AKT和ENOS中，激活磷酸化的磷酸化与肥胖诱导的高血压（HTN）相关，因此将全球FC riib - / - 小鼠放置在高脂饮食（HFD）上，并且发现尽管体重增加与FC？riib+/+null小鼠的体重增加相等。该提案的总体目标是确定FC？RIIB如何促进肥胖引起的HTN发病机理。 AIM 1是确定内皮细胞FC？RIIB如何参与该疾病。使用radiotelemetry，将在野生型小鼠与内皮细胞特异性FC riiB缺失的野生型小鼠中进行比较BP。 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，并将在内皮中选择性地表达组成型AKT的小鼠中评估HTN的潜在保护。将使用抗FC？RIIB阻断抗体来确定针对受体的干预措施是否阻止了HTN。目的2是识别介导肥胖引起的HTN的FC？riib配体。我们发现，HFD上小鼠的SAP增加，并且从HFD喂养的小鼠中分离出的IgG有效地拮抗培养的内皮中的eNOS，而来自正常食物喂养的小鼠的IgG却没有。因此，将研究HFD诱导的HTN在野生型与SAP - / - 和免疫球蛋白U重链无链无小鼠中缺乏B细胞和IgG中。如果这项工作暗示IgG，则使用增强IgG降解的B细胞耗尽抗体和FCRN指导的剂来确定降低FC的干预措施是否降低了FC？riiB配体丰度可预防肥胖症诱导的HTN。 AIM 3是确定FC？RIIB如何影响pentraxin水平或肥胖症升高的人类HTN的发展。 FC RIIB中常见的单核苷酸多态性（SNP）与事件HTN之间的关联将在女性基因组健康研究中进行评估，这是一项针对25,000多名女性的前瞻性队列研究。动力包括在达拉斯心脏研究中发现了无eNOS拮抗作用的FC？riib变体和具有CRP> 2.0mg/L的受试者的初步查询；在基因型频率提供足够统计能力的非裔美国人中，功能丧失变体与较低的收缩压BP有关。通过实现这些目标，将测试新颖的概念，即内皮中的FC riib和FCR配体参与HTN的发病机理。与肥胖症和其他慢性炎症状况复杂化的HTN的独特预防或治疗措施可能会遵循。