TSP1-CD47 in Promotion of PAH-Associated Vasoconstriction and Vascular Overgrowth

TSP1-CD47 促进 PAH 相关血管收缩和血管过度生长

• 批准号: 8155254
• 负责人: Jeffrey S Isenberg
• 金额: $ 37.89万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8155254
• 关键词: Affect; Anatomy; Angiogenic Proteins; Animals; Binding; Blood Platelets; Blood Vessels; Blood flow; Bone Marrow Transplantation; CD47 gene; Cells; Cessation of life; Chronic; Chronic lung disease; Coupled; Data; Disease; Effectiveness; Endothelial Cells; Experimental Models; Failure; Functional disorder; Gap Junctions; Gold; Growth; Growth Factor; Heart; Heart failure; Human; Hypertrophy; Hypoxia; In Vitro; Inflammatory; Interruption; Knockout Mice; Life; Ligands; Link; Liver; Location; Lung; Lung diseases; Malignant Neoplasms; Mediator of activation protein; Molecular; Monocrotaline; Mus; Nitric Oxide; PDGFRB gene; Pathogenesis; Pathologic; Pathway interactions; Patients; Physiological; Platelet-Derived Growth Factor; Play; Pre-Clinical Model; Principal Investigator; Process; Production; Progressive Disease; Proteins; Proto-Oncogene Proteins c-akt; Pulmonary Vascular Resistance; Pulmonary artery structure; Regulation; Resistance; Respiratory physiology; Response Elements; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Source; System; Testing; Therapeutic Effect; Thrombospondin 1; Up-Regulation; Vascular Diseases; Vascular remodeling; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Work; autocrine; base; cell growth; constriction; cytokine; gene function; human NOS3 protein; in vivo; migration; new therapeutic target; novel; prevent; promoter; pulmonary arterial hypertension; pulmonary artery endothelial cell; receptor; response; second messenger; stem; therapeutic target; vascular smooth muscle cell proliferation; vasoconstriction

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries marked by a progressive increase in pulmonary vascular resistance, leading to right heart failure and ultimately death. An imbalance between vasoconstriction and vasodilation coupled with vascular remodeling and overgrowth are hallmarks of PAH. Nitric oxide (NO) is known to play a protective role in PAH and endothelial failure and loss of NO signaling contribute to both human and experimental PAH. Recent work by the principal investigator has found that the matrix protein thrombospondin-1 (TSP1) blocks physiologic NO responses in vascular cells. Preliminary data suggests that TSP1, in binding to its necessary receptor CD47, inhibits activation of endothelial nitric oxide synthase (eNOS) and thus endothelial NO production, and that TSP1 and CD47 are dramatically upregulated in human and experimental PAH. Additional new data demonstrates that the TSP1-CD47 nexus stimulates vascular smooth muscle cell overgrowth in a PDGF-dependent manner in PAH. The central hypothesis to be tested in this proposal is that excessive TSP1 expression underlies PAH vasculopathy and that interaction with its cognate receptor, CD47, selectively regulates key second messenger pathways linked to microvascular vasoreactivity, growth, and remodeling. The present proposal will explore (i) the mechanisms behind upregulation of TSP1-CD47 in PAH, (ii) the implications this has on vascular tone and overgrowth and (iii) the effects that therapeutic interruption of the nexus has on preventing PAH and on ameliorating established disease. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) is a progressive disease that can occur without an identifiable cause or as a consequence of a number of chronic diseases of the lung, heart and liver. In all instances the disease leads to changes in lung function and blood flow that ultimately results in heart failure and death. There are no known cures and available therapy does little to stem the process or extend life. Central to the pathogenesis of PAH is concurrent changes in lung blood vessels that block flow from concurrent increased arterial constriction and thickening of smooth muscle cell layers in small pulmonary arteries. Nitric oxide (NO) is a natural biogas that promotes blood flow and vasodilation in pulmonary blood vessels. Loss of NO signaling is found in PAH and currently useful therapies target NO and try to increase this agent in the lung. Another central mediator of PAH is the smooth muscle cell growth factor platelet derived growth factor (PDGF). We have discovered a novel ligand-receptor interaction between thrombospondin-1 and CD47 that serves as a master regulator of both NO and PDGF. We have also found dramatic upregulation of the TSP1-CD47 nexus in human and several experimental models of PAH. Therapeutics that target the TSP1-CD47 pathway maximize NO and increase blood flow while simultaneously inhibiting smooth muscle cell hypertrophy and arterial thickening. In this proposal we will test the hypothesis that TSP1 promotes PAH through multiple pathways and that blocking TSP1 will both prevent and ameliorate PAH.

描述（由申请人提供）：肺动脉高压（PAH）是一种小肺动脉疾病，其特征是肺血管阻力进行性增加，导致右心衰竭并最终死亡。血管收缩和血管舒张之间的失衡以及血管重塑和过度生长是PAH的标志。已知一氧化氮（NO）在PAH中起保护作用，内皮功能衰竭和NO信号转导的丧失有助于人类和实验性PAH。主要研究者最近的工作发现，基质蛋白血小板反应蛋白-1（TSP 1）阻断血管细胞中的生理性NO反应。初步数据表明，TSP 1，在结合其必要的受体CD 47，抑制内皮型一氧化氮合酶（eNOS）的激活，从而内皮NO的生产，和TSP 1和CD 47显着上调人类和实验性PAH。额外的新数据表明，TSP 1-CD 47连接以PDGF依赖性方式刺激PAH中的血管平滑肌细胞过度生长。本提案中待检验的中心假设是，过度TSP 1表达是PAH血管病变的基础，与其同源受体CD 47的相互作用选择性调节与微血管血管反应性、生长和重塑相关的关键第二信使途径。本提案将探讨（i）PAH中TSP 1-CD 47上调背后的机制，（ii）这对血管张力和过度生长的影响，以及（iii）治疗中断关系对预防PAH和改善已建立疾病的影响。 公共卫生相关性：肺动脉高压（PAH）是一种进行性疾病，可能在没有可识别原因的情况下发生，也可能是肺、心脏和肝脏的许多慢性疾病的结果。在所有情况下，这种疾病都会导致肺功能和血流的变化，最终导致心力衰竭和死亡。目前还没有已知的治疗方法，可用的治疗方法对阻止这一过程或延长生命几乎没有作用。PAH发病机制的核心是肺血管的并发变化，其阻断了同时增加的动脉收缩和小肺动脉中平滑肌细胞层增厚引起的血流。一氧化氮（NO）是一种天然的生物气，可促进肺血管中的血液流动和血管舒张。在PAH中发现NO信号传导的丧失，目前有用的治疗靶向NO并试图增加肺中的这种药剂。PAH的另一个中心介质是平滑肌细胞生长因子血小板衍生生长因子（PDGF）。我们已经发现了一种新的血小板反应蛋白-1和CD 47之间的配体-受体相互作用，作为NO和PDGF的主调节器。我们还发现在人类和几种PAH实验模型中TSP 1-CD 47连接显著上调。靶向TSP 1-CD 47通路的治疗剂使NO最大化并增加血流量，同时抑制平滑肌细胞肥大和动脉增厚。在这项提案中，我们将测试TSP 1通过多种途径促进PAH的假设，阻断TSP 1将预防和改善PAH。