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都参与了 PAH 的发病机制。然而，触发机制和疾病维持机制仍然难以捉摸。 根据关节炎、肾病和癌症等其他疾病的新证据，得出 通过该项目的联合研究人员发现，很明显，当补体系统失调时， 可以成为炎症驱动的组织损伤的有力煽动者。我们最近发布的数据 我们相信这是第一次证明，免疫球蛋白驱动的补体激活 肺血管周围区域的级联，特别是其替代途径，是一个关键机制 在实验性低氧 PH 中启动促炎和促增殖过程（一种“无菌形式”） 炎症”）。我们还证明了激活的补体级联和免疫球蛋白 G (IgG) 沉积是疾病的持久决定因素。本提案建立在这些发现的基础上 包括机械臂和平移臂。在目标 1 中，我们将评估免疫球蛋白的作用 和补体启动 PH 中的促炎过程。在目标 2 中，我们将评估 免疫球蛋白和补体在血管损伤和疾病过程持续进展中的作用。在 潜在的高度转化目标 3 我们将测试靶向（局部）补体抑制的功效 使用新型补体抑制剂（称为 TT32 的人类融合蛋白）进行实验 PH，可用于 靶向局部激活的补体信号传导。