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

项目摘要 白细胞介素6（IL-6）反式信号传导是一种非经典信号传导模式，其在人类中通过 IL-6 R Ala 358同种型（rs 2228145; Asp 358 Ala），一种在多个细胞中以高频率出现的变体， 种族新出现的证据表明，IL-6反式信号转导有助于心血管（CV）疾病 IL 6 R Ala 358变异体是心力衰竭患者致死性CV结局的预测因子 （HF）.因此，IL 6 R Ala 358变异体可能是疾病风险和对IL 6 R应答的重要分层因素。 在CV疾病或HF受试者中靶向IL-6反式信号传导的治疗。 鉴于IL-6 R Ala 358在人群中的高患病率，其与不良CV结局的联系，IL-6 反式信号在心脏纤维化的发展，以及药理学策略的可用性，它是 证实IL-6受体Ala 358在心脏炎症和纤维化中的作用以及IL-6反式信号传导 阻断是一种有效的治疗策略。在这个应用中，我们将使用经主动脉缩窄， 在我们的IL-6反式信号传导的新型C57 BL/6 Il 6 raE 357 A小鼠模型中的心脏压力超负荷（PO）。我们 假设响应于压力超负荷（PO）产生的增加的循环IL-6将 在存在增强的IL-6反式信号传导的情况下加剧心脏纤维化和HF， C57 BL/6 Il 6 raE 357 A基因型和用sgpl 30 Fc治疗将预防或减弱心脏纤维化， HF。使用最先进的空间转录组学，我们将识别心脏的具体类型和位置 对IL-6反式信号传导有反应的细胞。该项目的目标是： 目标1.评估C57 BL/6 Il 6 raE 357 A小鼠增强的sIL-6 R脱落基因型的影响， IL-6反式信号转导对PO诱导的心脏纤维化和左心室功能障碍的影响 目标二。确定选择性IL-6反式信号传导阻断与sgp 130 FC阻断是否有效 改善PO诱导的心脏纤维化的策略。 这些实验将确立增强的IL-6反式信号传导是否增加心脏 纤维化和HF风险。我们还将探索特定的细胞机制，采用先进的空间 转录组学，其允许鉴定受IL-6反式信号传导影响的心脏细胞类型和位置。 此外，鉴于sgp 130 Fc目前处于II期临床试验（商品名Olamkicept），我们将 建立有效的生物学模型，研究IL-6转译信号转导的翻译价值。

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.