Bone marrow-derived precursor cells and angioproliferative PH

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）源性前体细胞。肺动脉高压（PH）的发病率似乎在增加，这也可能与超声心动图的更常见使用导致的更频繁的诊断有关。PH也被认为是间质性肺病患者死亡率增加的指标。在达纳角召开的第四届世界卫生组织会议更新了严重PH的病理生物学概念，但迄今尚未发现治愈性治疗方法。血管增生性病变中的细胞是抗血管增生的，近年来已经产生了大量关于BM来源的前体细胞对血管重塑的贡献的信息，但尚未研究BM来源的前体细胞是否参与PAH中血管增生性病变的发展。本课题组建立了SU 5416/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，BM来源的前体细胞是重要的，并有助于通过生长因子的生产和移植到血管壁的血管增生性病变的发展。我们的初步数据表明，在SuHx动物的小肺动脉内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分析作为工具，以阐明骨髓源性前体细胞在严重实验性PAH血管增生性病变发展中的作用。将在两个特定目的中检验BM源性前体细胞显著促进PAH中血管增殖的假设：在特定目的1中，我们将回答在重度血管增殖性PAH中，BM源性前体细胞是否在血管增殖性病变和血液中增加，并显示生长因子的产生增强的问题。在特定目标2中，我们将研究严重血管增生性PAH中BM源性前体细胞募集至肺血管的机制。我们将专门研究细胞凋亡抑制和阻断CXCR 4是否会减少前体细胞归巢，血管增殖和PH。总之，本项目旨在证明BM衍生的前体细胞通过生长因子的产生和植入血管壁促进PAH的血管增殖。

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.