Cincinnati Center of Excellence in Hemoglobinopathies Research

描述（由申请人提供）： 心肺肾并发症是目前镰状细胞病（SCD）最常见的死亡原因。心血管病理学被慢性贫血的影响所掩盖：存在双心室肥大但射血分数正常。左心室舒张功能障碍和不明原因的猝死也很常见。SCD患者的肺动脉高压（PAH）是近年来研究和争论的焦点。在几项研究中，通过三尖瓣反流射流速度（TRV）>2.5m/s估计的肺动脉（PA）压力轻度升高与高死亡率相关。然而，心脏导管检查诊断PAH仅存在于TRV>2.5m/s的患者中的25-33%。然而，即使PA压力非常轻微升高的SCD患者的不良事件数量也出乎意料地高，其机制尚不清楚。高TRV与SCD的肾脏病理密切相关。基于我们的初步数据，我们假设活性氧（ROS）和血管紧张素11（AT）-AT 1受体（AT 1 R）在SCD中被激活，产生TGF β 1，TGF β 1是一种促纤维化血栓炎性细胞因子，通过引起促纤维化状态和独特的限制性心肌病（RCM）伴继发性PAH介导SCD心肾疾病和猝死。我们将（目的1）测试SCD中增加的ROS是否是通过RAS介导的G-蛋白信号传导来衍生的，以使用药理学或遗传方法恶化氧化膜损伤和溶血，并研究ROS对心肾病理的影响;（目的2）检查心脏或肾AT 1 R信号传导或TGF？1的生产，特别是在心脏或肾脏组织中使用缺乏AT 1 R或TGF β 1的小鼠。我们还将研究TGF？？1来源于血小板，循环TGF？？1的TGP？？1，特别是在血小板和研究对心肾病理的影响;（目的3）探索新的心脏MR模式，以检测独特的限制性心肌病和量化弥漫性心肌纤维化的SCD患者与高TRV。同样的新型CMR成像也将在小鼠中进行，其中成像可以与解剖学和组织病理学分析相关联。血液学、心脏病学和放射学、药理学和遗传学方法以及平行人体研究的多学科研究者组成的多元化团队将允许对SCD中的心肾病理进行多方面分析，以允许将研究发现快速转化为治疗靶点和未来的II/III期试验。 (End摘要）

DESCRIPTION (provided by applicant): Cardiopulmonary-renal complications are now the most common cause of mortality in sickle cell disease (SCD). Cardiovascular pathology is overshadowed by the effects of chronic anemia: presence of biventricular hypertrophy but normal ejection fractions. Left ventricular diastolic dysfunction and sudden unexplained deaths also occur commonly. Pulmonary artery hypertension (PAH) in SCD has been the focus of recent research and debate. Mildly elevated pulmonary arterial (PA) pressures, estimated by a tricuspid regurgitation jet velocity (TRV)>2.5m/s have been associated with high mortality in several studies. However, cardiac catheterization diagnosed PAH is only present in 25-33% of those with TRV>2.5m/s. Nevertheless, the number of adverse events in SCD patients with even very mild elevation in PA pressures is unexpectedly high and its mechanism/s is unknown. High TRV strongly associates with renal pathology in SCD. Based upon our preliminary data, we hypothesize that reactive oxygen species (ROS) and angiotensin 11 (AT)-AT1 receptor (AT1R) is activated in SCD to generate TGFP1, a profibrotic thrombo-lnflammatory cytokine that mediates SCD cardio-renal disease and sudden death, by causing a profibrotic state and a unique restrictive cardiomyopathy (RCM) with secondary PAH. We will {Aim 1) test whether the' increased ROS in SCD is derived via RAS-mediated G-protein signaling to worsen oxidative membrane damage and hemolysis using pharmacological, or genetic approaches and study the effects of ROS on cardio-renal pathologies; {Aim 2) examine the relative contribution of cardiac or renal AT1R signaling or TGF?1 production using mice deficient in AT1R or TGFbeta1 specifically in cardiac or renal tissues. We will also study the effects of TGF??1 derived from platelets, the largest source of circulating TGF??1 by using mice deficient in TGP??1 specifically in platelets and study the effect on cardio-renal pathology; and (Aim 3) explore novel cardiac MR modalities to detect the unique restrictive cardiomyopathy and quantify diffuse myocardial fibrosis in patients with SCD with and without high TRV. The same novel CMR imaging will also be done in mice, where imaging can be correlated with anatomical and histopathological analysis. The diverse team of multidisciplinary investigators in hematology, cardiology and radiology, pharmacological and genetic approaches, and parallel human studies will allow a multifaceted analysis of the cardio-renal pathologies in SCD, to allow rapid translation of research discoveries into therapeutic targets and a future phase ll/lll trials. (End of Abstract)