Golgi Blockade in Pulmonary Hypertension

肺动脉高压中的高尔基体阻断

• 批准号: 7790624
• 负责人: PRAVIN B SEHGAL
• 金额: $ 39.75万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-07 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7790624
• 关键词: Apoptosis; BMPR2 gene; Blood Vessels; CD31 Antigens; Cell Culture Techniques; Cell Line; Cell Size; Cells; Clathrin; Complex; DNA biosynthesis; Defect; Disease; Distal; Endoplasmic Reticulum; Endothelial Cells; Equus caballus; Etiology; Event; Experimental Models; Exposure to; Figs - dietary; Functional disorder; Genetic; Glycoproteins; Golgi Apparatus; Growth Factor; Growth Factor Receptors; Human; Hypoxia; Investigation; Kinetics; Lead; Lesion; Life; Link; Lung; Lung diseases; Membrane; Membrane Protein Traffic; Modeling; Monocrotaline; Morbidity - disease rate; Movement; Muscle; Mutation; N-ethylmaleimide-sensitive protein; Pathogenesis; Peroxidases; Predisposing Factor; Progressive Disease; Proteins; Pulmonary Hypertension; Pyrroles; Radish; Rattus; Reaction; Resistance; S-nitro-N-acetylpenicillamine; SNAP receptor; Signal Transduction; Smooth Muscle Myocytes; Thinking; Transgenic Mice; Vesicle; arterial lesion; caveolin 1; cell motility; cytokine; in vivo; macrogolgin; man; mimetics; mortality; mutant; novel; public health relevance; pulmonary arterial hypertension; receptor; research study; response; syntaxin 4; trafficking

DESCRIPTION (provided by applicant): Pulmonary hypertension (PH) is a progressive disease with high morbidity and mortality with mutations in BMPR2 a predisposing factor in this disease. A hallmark of the subcellular alterations in this disease, in man and in experimental models, includes enlarged vacuolated endothelial and smooth muscle cells with increased endoplasmic reticulum and Golgi stacks ("megalocytosis") in pulmonary arterial lesions. We propose a novel disease-initiating mechanism at the subcellular level - a dysfunction of intracellular trafficking (the Golgi blockade hypothesis). We shall investigate this mechanism in human PH and in experimental models (monocrotaline, hypoxia, BMPR2R899X mutation) using in vivo-derived materials and in experiments in cell culture. Predicted consequences include trapping of vesicle tethers, SNAREs and SNAPs in the Golgi and subcellular mislocalization of N-ethylmaleimide sensitive factor (NSF), and of cargo such as eNOS and vasorelevant growth factor recetors (SNAREing pulmonary hypertension), Distal consequences include enhanced cytokine and growth factor signaling, promitogenic signaling and DNA synthesis, resistance to apoptosis, increased cell size and cell migration and thus reduction of the vascular lumen. In Aim 1 (in vivo studies) we shall link the Golgi blockade hypothesis to the pathophysiology of idiopathic PH in man, in the monocrotaline and hypoxia models of PH in the rat, and in the BMPR2 R899X transgenic mouse. In Aim 2 (cell culture studies) we shall investigate the initiation mechanisms that lead to Golgi blockade and defects in intracellular trafficking in response to MCTP, hypoxia and BMPR2 mutants with a focus on NSF and the proximal mechanistic events involved. In Aim 3 (cell culture studies) we shall investigate some of the distal trafficking consequences of disruption of intracellular trafficking by MCTP, hypoxia and BMPR mutants. PUBLIC HEALTH RELEVANCE. Pulmonary arterial hypertension (PH) is a progressive fatal lung disease in man. We propose an all together novel way of thinking about the cause of this fatal disease. We suggest that the endothelial and smooth muscle cells that line the arterial blood vessels in the lung become bigger and increase in number because of a defect in cellular machinery that handles the movement of proteins within these cells. This leads to a blockage of the blood vessels. The proposed mechanism opens up new ways of thinking about how to treat this disease.

描述（由申请人提供）：肺动脉高压（PH）是一种进行性疾病，发病率和死亡率较高，BMPR 2突变是该疾病的诱发因素。在人类和实验模型中，这种疾病的亚细胞改变的标志包括肺动脉病变中的增大的空泡化内皮细胞和平滑肌细胞，以及增加的内质网和高尔基体堆积（“巨细胞增多症”）。我们提出了一种新的疾病引发机制在亚细胞水平-细胞内运输功能障碍（高尔基体阻断假说）。我们将在人体PH和实验模型（野百合碱，缺氧，BMPR 2 R899 X突变）中使用体内衍生材料和细胞培养实验研究这种机制。预测的结果包括囊泡栓系、SNARE和SNAP在高尔基体中的捕获以及N-乙基马来酰亚胺敏感因子（NSF）和货物如eNOS和血管相关生长因子受体的亚细胞错误定位远端后果包括增强的细胞因子和生长因子信号传导、促有丝分裂信号传导和DNA合成、对细胞凋亡的抗性，增加的细胞大小和细胞迁移，从而减少血管腔。在目标1（体内研究）中，我们将高尔基体阻断假说与人类特发性PH、大鼠PH的野百合碱和缺氧模型以及BMPR 2 R899 X转基因小鼠的病理生理学联系起来。在目标2（细胞培养研究）中，我们将研究导致高尔基体阻断和细胞内运输缺陷的起始机制，以响应MCTP，缺氧和BMPR 2突变体，重点关注NSF和相关的近端机制事件。在目标3（细胞培养研究）中，我们将研究MCTP、缺氧和BMPR突变体破坏细胞内运输的一些远端运输后果。公共卫生相关性。肺动脉高压（PH）是一种进行性的致命性肺部疾病，我们提出了一种全新的思路来思考这种致命性疾病的原因。我们认为，排列在肺动脉血管中的内皮细胞和平滑肌细胞变得更大，数量增加，因为处理这些细胞内蛋白质运动的细胞机制存在缺陷。这会导致血管堵塞。提出的机制为如何治疗这种疾病开辟了新的思路。