Bone marrow-derived precursor cells and angioproliferative PH

骨髓源性前体细胞和血管增殖性 PH

• 批准号: 8302191
• 负责人: NORBERT F VOELKEL
• 金额: $ 18.69万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302191
• 关键词: Animals; Apoptosis; Apoptotic; Blood; Blood Vessels; Bone Marrow; CXCL12 gene; CXCR4 gene; Caspase Inhibitor; Cells; Chronic; Data; Development; Diagnosis; Disease; Echocardiography; Engraftment; Flow Cytometry; Gene Expression Profiling; Growth Factor; Homing; Hypoxia; Incidence; Inhibition of Apoptosis; Interstitial Lung Diseases; Lesion; Lung; Modeling; Patients; Platelet-Derived Growth Factor; Production; Pulmonary Hypertension; Pulmonary artery structure; Resistance; Role; SU 5416; Sum; Techniques; Testing; Update; Vascular Endothelial Growth Factors; Vascular remodeling; interstitial; mortality; novel therapeutics; precursor cell; pulmonary arterial hypertension; reconstitution; research study; symposium; tool

DESCRIPTION (provided by applicant): This application aims to investigate bone marrow (BM)-derived precursor cells in the context of severe, angioproliferative pulmonary arterial hypertension (PAH, a group of nearly always lethal diseases. The incidence of pulmonary hypertension (PH) appears to be increasing, which might also be related to more frequent diagnosis due to more common use of echocardiography. PH has also been recognized as an indicator of increased mortality in patients with interstitial lung diseases. The 4th WHO conference in Dana Point updated the pathobiological concepts of severe PH, yet no curative therapy has been found so far. It is increasingly acknowledged that the cells in the angioproliferative lesions are apoptosis-resistant, and the recent years have generated substantial information about the contribution of BM-derived precursor cells to vascular remodeling, but it has not been investigated whether or not BM-derived precursor cells participate in the development of angioproliferative lesions in PAH. Our group has established the SU5416/chronic hypoxia (SuHx) model as a model of severe angioproliferative PAH. Our central hypothesis is that BM-derived precursor cells are important and contribute to the development of angioproliferative lesions via growth factor production and engraftment into the vessel wall. Our preliminary data indicate the presence of pluripotent cells in and around small pulmonary arteries in SuHx animals. In the course of the proposed experiments, we will establish various techniques, including BM reconstitution and FACS analysis as tools to elucidate the role of bone-marrow derived precursor cells in the development of angioproliferative lesions in severe experimental PAH. The hypothesis that BM-derived precursor cells contribute significantly to angioproliferation in PAH will be tested in two Specific Aims: In Specific Aim 1, we will answer the question whether BM-derived precursor cells are increased in angioproliferative lesions and blood, and show enhanced production of growth factors, in severe, angioproliferative PAH. In Specific Aim 2, we will investigate the mechanisms of BM-derived precursor cell recruitment into the pulmonary vasculature in severe angioproliferative PAH. We will specifically examine whether apoptosis inhibition and blocking CXCR4 will decrease precursor cell homing, angioproliferation and PH. In sum, this project aims to demonstrate that BM-derived precursor cells contribute to angioproliferation in PAH via growth factor production and engraftment into the vessel wall.

描述（由申请人提供）：本申请旨在研究严重血管增生性肺动脉高压（PAH，一组几乎总是致命的疾病）背景下的骨髓（BM）来源的前体细胞。肺动脉高压（PH）的发生率似乎正在增加，这也可能与由于超声心动图的更广泛使用而导致的更频繁的诊断有关，PH也被认为是间质性肺疾病患者死亡率增加的一个指标。 Dana Point 更新了严重 PH 的病理学概念，但迄今为止尚未找到治疗方法 人们越来越认识到血管增生性病变中的细胞具有抗凋亡能力，近年来已经产生了大量关于 BM- 的贡献的信息。衍生的前体细胞参与血管重塑，但尚未研究BM衍生的前体细胞是否参与PAH中血管增殖性病变的发展。我们课题组建立了SU5416/慢性缺氧（SuHx）模型作为重度血管增生性PAH模型。我们的中心假设是，骨髓来源的前体细胞很重要，并通过生长因子的产生和植入血管壁促进血管增殖性病变的发展。我们的初步数据表明 SuHx 动物的小肺动脉内部和周围存在多能细胞。在拟议的实验过程中，我们将建立各种技术，包括 BM 重建和 FACS 分析，作为阐明骨髓源性前体细胞在严重实验性 PAH 血管增殖病变发展中的作用的工具。 BM 衍生的前体细胞对 PAH 中的血管增殖有显着贡献的假设将在两个具体目标中进行测试：在具体目标 1 中，我们将回答 BM 衍生的前体细胞是否在血管增生性病变和血液中增加，并显示出产量增加的问题生长因子在严重的血管增生性 PAH 中的作用。在具体目标 2 中，我们将研究严重血管增生性 PAH 中骨髓源性前体细胞募集至肺血管系统的机制。我们将具体检查细胞凋亡抑制和阻断 CXCR4 是否会降低前体细胞归巢、血管增殖和 PH。总之，该项目旨在证明骨髓来源的前体细胞通过生长因子的产生和植入血管壁来促进 PAH 中的血管增殖。