A novel, genetic model of IL-6 trans-signaling to interrogate cardiac fibrosis pathology

用于研究心脏纤维化病理学的新型 IL-6 信号转导遗传模型

• 批准号: 10667223
• 负责人: GREGORY A HAWKINS
• 金额: $ 23.25万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-21 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667223
• 关键词: Affect; African; Attenuated; Binding; Biological Assay; Biological Markers; Biological Models; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cells; Clinical; Complex; Data; Development; Disease; Ethnic Origin; European; Exhibits; Fibrillar Collagen; Fibroblasts; Frequencies; Functional disorder; Gene Expression; General Population; Genetic Models; Genetic Polymorphism; Genotype; Goals; Heart failure; Hepatocyte; High Prevalence; Histologic; Human; Inflammatory; Interleukin 6 Receptor; Interleukin-6; Left; Left Ventricular Dysfunction; Leukocytes; Link; Location; Measures; Membrane; Modeling; Mus; Mutation; Myocarditis; Names; National Institute of Allergy and Infectious Disease; Native American Ancestry; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Phase II Clinical Trials; Phenotype; Play; Population; Production; Protein Isoforms; Risk; Role; Signal Transduction; Stratification Factors; Therapeutic Intervention; Tissues; Variant; Ventricular; antifibrotic treatment; aorta constriction; cell type; coronary fibrosis; disorder risk; effective therapy; experimental study; extracellular; glycoprotein 130; heart function; high risk; insight; interstitial; mouse model; novel; patient stratification; pharmacologic; pressure; prevent; response; targeted treatment; transcriptomics; treatment response; treatment strategy

Project Summary Interleukin 6 (IL-6) trans-signaling is a non-canonical signaling paradigm that is greatly enhanced in humans by the IL-6R Ala358 isoform (rs2228145; Asp358Ala), a variant that occurs at a high frequency across multiple ethnicities. Emerging evidence suggests that IL-6 trans-signaling contributes to cardiovascular (CV) disease pathogenesis and that the IL6R Ala358 variant is a predictor of fatal CV outcomes in patients with heart failure (HF). Thus the IL6R Ala358 variant may be an essential stratification factor for disease risk and response to therapies targeting IL-6 trans-signaling in subjects with CV disease or HF. Given the high prevalence of IL6R Ala358 in the population, its link to adverse CV outcomes, evidence of IL-6 trans-signaling in the development of cardiac fibrosis, and the availability of pharmacological strategy, it is fundamental to confirm the role of IL6R Ala358 in cardiac inflammation and fibrosis and that IL-6 trans-signaling blockade is an effective treatment strategy. In this application, we will use trans-aortic constriction to cause cardiac pressure overload (PO) in our novel C57BL/6 Il6raE357A mouse model of IL-6 trans-signaling. We hypothesize that increased circulating IL-6 produced in response to pressure overload (PO) will exacerbate cardiac fibrosis and HF in the presence of enhanced IL-6 trans-signaling determined by C57BL/6 Il6raE357A genotype and treatment with sgp130Fc will prevent or attenuate cardiac fibrosis and HF. Using state of the art spatial transcriptomics, we will identify the specific type and location of cardiac cells responsive to IL-6 trans-signaling. The goals of this project are: Aim 1. Assess the impact of the C57BL/6 Il6raE357A mouse genotype of enhanced sIL-6R shedding and IL-6 trans-signaling on PO-induced cardiac fibrosis and left ventricular dysfunction. Aim 2. Determine if selective IL-6 trans-signaling blockade with sgp130FC blockade is an effective strategy to ameliorate PO-induced cardiac fibrosis. These experiments will establish the proof-of-concept whether enhanced IL-6 trans-signaling increases cardiac fibrosis and HF risk. We will also explore specific cellular mechanisms by employing advanced spatial transcriptomics, which allows the identification of cardiac cell type and location affected by IL-6 trans-signaling. Additionally, given that he sgp130Fc is currently in phase II clinical trials (trade name Olamkicept) we will have establish a validated biological model to study IL-6 trans-signaling with translational value.

项目摘要 白介素6(IL-6)反式信号传递是一种非规范的信号传递范式，通过以下方式在人类中得到极大的增强 IL-6R Ala358亚型(rs2228145；Asp358Ala)，一种在多个 种族。新的证据表明，IL-6反式信号转导与心血管疾病有关 IL6R Ala358变异是心力衰竭患者致死性心血管结局的预测因子 (Hf)。因此，IL6R Ala358变异体可能是疾病风险和反应的重要分层因素 针对心血管疾病或心衰受试者的IL-6转导信号的治疗。 鉴于IL6R Ala358在人群中的高患病率，其与不良心血管结局的联系，IL-6的证据 反式信号转导在心脏纤维化发展中的作用，以及药物策略的有效性，它是 确认IL6R Ala358在心脏炎症和纤维化中的作用以及IL-6转导信号的基础 封锁是一种有效的治疗策略。在本应用中，我们将使用经主动脉缩窄来引起 我们的新型IL-6反式信号转导C57BL/6 Il6raE357A小鼠模型中的心脏压力超负荷(PO)。我们 假设压力超负荷(PO)时产生的循环IL-6增加将 在IL-6反式信号增强的情况下加剧心肌纤维化和心力衰竭 C57BL/6 Il6raE357A基因型和sgp130Fc治疗将预防或减轻心肌纤维化和 高频。利用最先进的空间转录技术，我们将确定心脏的特定类型和位置 对IL-6转导信号有反应的细胞。该项目的目标是： 目的1.评估C57BL/6 Il6raE357A小鼠基因型对增强型sIL-6R脱毛和 IL-6反式信号转导在PO诱导的心肌纤维化和左心功能不全中的作用 目的2.确定sgp130Fc阻断选择性IL-6转导信号是否有效 改善PO诱导的心肌纤维化的策略。 这些实验将建立概念验证，即增强的IL-6转导信号是否会增加心脏 纤维化和心力衰竭的风险。我们还将通过使用高级空间技术来探索特定的细胞机制 转录学，它允许识别受IL-6反式信号影响的心肌细胞类型和位置。 此外，鉴于sgp130Fc目前处于第二阶段临床试验(商标为Olamkicept)，我们将有 建立有效的生物学模型来研究具有翻译价值的IL-6反式信号转导。