Immunoglobulin-Driven Activation of the Complement Cascade is a Critical Determinant of PAH Initiation and Progression

免疫球蛋白驱动的补体级联激活是 PAH 发生和进展的关键决定因素

• 批准号: 10686929
• 负责人: Kurt R. Stenmark
• 金额: $ 47万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686929
• 关键词: Area; Arthritis; Autoantibodies; Autoimmune; Autoimmune Diseases; Binding; Biological Markers; Blood Vessels; Cells; Chimeric Proteins; Clinical; Complement; Complement 3d; Complement Activation; Complement Inactivators; Data; Deposition; Diagnosis; Disease; Epitope spreading; Epitopes; Goals; Human; Hypertension; Hypoxia; Immune; Immune response; Immunoglobulin G; Immunoglobulins; Inflammation; Inflammatory; Injury; Kidney Diseases; Life Expectancy; Lung; Malignant Neoplasms; Mediating; Natural Immunity; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Plasma; Process; Prognostic Factor; Publishing; Pulmonary Heart Disease; Pulmonary Hypertension; Research Personnel; Rodent; Role; Signal Transduction; Sterility; Stimulus; Testing; Time; Vascular remodeling; X-Ray Computed Tomography; arm; complement system; diagnostic biomarker; efficacy testing; in vivo; lung vascular injury; natural antibodies; neoantigens; novel; pulmonary arterial pressure; pulmonary vascular disorder; pulmonary vascular remodeling; recruit; single photon emission computed tomography; targeted delivery; targeted treatment; therapeutic target; tissue injury; vascular inflammation; vascular injury

There is convincing evidence for both inflammatory and autoimmune phenomena to be involved in the pathogenesis of PAH. However, both the triggering and the disease sustaining mechanisms remain elusive. Based on emerging evidence in other diseases, including arthritis, kidney disease, and cancer, generated by Co-Investigators on this project, it has become clear that the Complement system, when dysregulated, can become a potent instigator of inflammation-driven tissue injury. Our recently published data demonstrated, we believe for the first time, that the immunoglobulin-driven activation of the complement cascade, specifically its alternative pathway, in the pulmonary perivascular areas is a critical mechanism initiating pro-inflammatory and pro-proliferative processes in experimental hypoxic PH (a form of “sterile inflammation”). We also demonstrated that the activated complement cascade and immunoglobulin G (IgG) deposition are persistent determinants of the disease. The present proposal builds on these findings and comprises both mechanistic and translational arms. In Aim 1 we will evaluate the role of immunoglobulins and complement in initiation of pro-inflammatory processes in PH. In Aim 2 we will evaluate the role of immunoglobulins and complement in the sustained progression of vascular injury and the disease process. In a potentially highly translational Aim 3 we will test the efficacy of targeted (local) complement inhibition in experimental PH using a novel complement inhibitor, human fusion protein termed TT32, which can be used to target local activated complement signaling.

有令人信服的证据表明炎症和自身免疫现象参与 PAH的发病机理。但是，触发和疾病的持续机制均难以捉摸。 基于其他疾病的新证据，包括关节炎，肾脏疾病和癌症 通过该项目的共同投资者，很明显，当不调节时，补体系统， 可能成为炎症驱动组织损伤的潜在刺激者。我们最近发布的数据 我们首次相信，通过免疫球蛋白驱动的激活 在肺周围区域中，级联级联是其替代途径 在实验性低氧pH（一种无菌形式 炎症”）。我们还证明了激活的补体级联反应和免疫球蛋白G（IgG） 沉积物是该疾病的持续决定者。本提案以这些发现为基础， 包括机械和翻译的手臂。在AIM 1中，我们将评估免疫球蛋白的作用 并补充pH中促炎过程的启动。在AIM 2中，我们将评估 免疫球蛋白和血管损伤持续发展和疾病过程中的完成。在 一个潜在的高度翻译目标3我们将测试目标（本地）完成抑制的效率 使用新型补体抑制剂的实验pH，称为TT32的人类融合蛋白可以使用 靶向局部激活的完成信号。