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这一过程。 PAH的发病机制。然而，触发和疾病维持机制仍然难以捉摸。 基于其他疾病的新证据，包括关节炎，肾脏疾病和癌症， 由该项目的共同研究者，很明显，补体系统，当失调时， 可能成为炎症驱动的组织损伤的有力煽动者。我们最近公布的数据 我们相信，这是第一次证明，免疫球蛋白驱动的补体激活 级联反应，特别是其旁路途径，在肺血管周围地区是一个关键机制 在实验性缺氧PH（一种“无菌”形式）中启动促炎和促增殖过程 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。本建议以这些调查结果为基础， 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 在目的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的持续进展中的作用。在 一个潜在的高度翻译的目标3，我们将测试靶向（局部）补体抑制的功效， 实验PH使用一种新的补体抑制剂，人融合蛋白TT32，它可以使用 靶向局部激活的补体信号传导。