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）：本申请旨在在严重的，血管增生性的肺动脉高压（PAH，几乎总是致命的疾病中）调查骨髓（BM）衍生的前体细胞（PAH）。肺部降压（pH）的发生率也与pH值更加常见，因为肺部的诊断可能还会更常见。室间肺部疾病患者的死亡率增加。但是尚未研究BM衍生的前体细胞是否参与PAH的血管增生性病变的发展。我们的小组已建立了SU5416/慢性缺氧（SUHX）模型，作为严重的血管增生性PAH的模型。我们的中心假设是，BM衍生的前体细胞很重要，并通过生长因子生产和植入血管壁有助于血管增生性病变的发展。我们的初步数据表明，Suhx动物中小肺动脉和周围存在多能细胞。在提出的实验过程中，我们将建立各种技术，包括BM重建和FACS分析，作为阐明骨row衍生的前体细胞在严重实验PAH中血管增生性病变发展中的作用的工具。 BM衍生的前体细胞的假说将在两个具体的目的中进行测试，这一假说有显着促进PAH的血管增生：在特定的目标1中，我们将回答以下问题，即BM衍生的前体细胞在血管增生性病变和血液中是否增加了BM衍生的前体细胞，并显示出生长因子增强的生长因子，在严重的，Angioperative pah的生长因子的产生中增强。在特定的目标2中，我们将研究BM衍生的前体细胞募集的机制，以在严重的血管增生性PAH中降低肺脉管系统。我们将特别检查凋亡抑制和阻断CXCR4是否会降低前体细胞归巢，血管增生和pH。总而言之，该项目旨在证明BM衍生的前体细胞通过生长因子的生产和植入到血管壁中有助于PAH的血管增生。