Cincinnati Center of Excellence in Hemoglobinopathies Research

辛辛那提血红蛋白病研究卓越中心

• 批准号: 8468307
• 负责人: Punam Malik
• 金额: $ 179.68万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468307
• 关键词: Adverse event; Anemia; Angiotensins; Blood Platelets; Cardiac; Cardiac Catheterization Procedures; Cardiology; Cardiopulmonary; Cardiovascular Pathology; Cessation of life; Chronic; Data; Diagnosis; Diffuse; EFRAC; Fibrosis; Functional disorder; Future; GTP-Binding Proteins; Genetic; Hematology; Hemoglobinopathies; Hemolysis; Human; Hypertension; Hypertrophy; Image; Kidney; Kidney Diseases; Left; Lung; Mediating; Membrane; Modality; Mus; Myocardial; Pathology; Patients; Phase; Production; Pulmonary artery structure; Radiology Specialty; Reactive Oxygen Species; Receptor Signaling; Relative (related person); Renal Tissue; Research; Research Personnel; Restrictive Cardiomyopathy; Sickle Cell Anemia; Signal Transduction; Source; Sudden Death; Testing; Translational Research; Tricuspid Valve Insufficiency; Ventricular; abstracting; base; cytokine; mortality; multidisciplinary; novel; pressure; receptor; therapeutic target

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)

描述(由申请人提供)： 心肺肾并发症现在是镰状细胞病(SCD)最常见的死亡原因。心血管病理被慢性贫血的影响所掩盖：存在双室肥厚，但射血分数正常。左室舒张功能不全和不明原因的猝死也很常见。SCD合并肺动脉高压(PAH)一直是近年来研究和争论的焦点。在多项研究中，通过三尖瓣返流速度和2.5m/S估计的轻度肺动脉压升高与高死亡率有关。然而，在TRV&GT；2.5m/S的患者中，心导管检查诊断为PAH的患者只有25%-33%。然而，即使是非常轻微的PA压升高，SCD患者的不良事件数量也出人意料地高，其机制尚不清楚/S。高TRV与SCD的肾脏病理密切相关。根据我们的初步数据，我们假设在SCD中，活性氧物种(ROS)和血管紧张素11(AT)-AT1受体(AT1R)被激活，从而产生TGFP1，这是一种促纤维化的血栓性炎症细胞因子，通过导致促纤维化状态和继发性PAH的独特的限制性心肌病(RCM)而介导SCD的心肾疾病和猝死。我们将{目标1)测试SCD中ROS增加是否通过RAS介导的G蛋白信号转导而来，从而使用药理学或遗传学方法加剧氧化膜损伤和溶血，并研究ROS对心肾病理的影响；{目标2)利用AT1R或TGFbeta1基因缺陷小鼠，研究心脏或肾脏AT1R信号转导或转化生长因子？1产生的相对贡献。我们还将利用TGP？1特异性缺失的小鼠，研究血小板来源的转化生长因子？1对循环中转化生长因子1的最大来源的影响，并研究其对心肾病理的影响；(目的3)探索新的心脏磁共振成像方法，以检测独特的限制性心肌病，并定量检测伴和不伴高TRV的SCD患者的弥漫性心肌纤维化。同样的新型CMR成像也将在小鼠身上进行，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的人体研究方面的多学科研究人员组成的多样化团队将允许对SCD的心肾病理进行多方面的分析，从而使研究发现能够快速转化为治疗目标和未来的11/11阶段试验。(摘要结束)