Bone marrow-derived precursor cells and angioproliferative PH

描述(申请人提供)：该申请旨在研究严重的血管增生性肺动脉高压(PAH)背景下的骨髓(BM)来源的前体细胞，这是一组几乎总是致命的疾病。肺动脉高压(PH)的发生率似乎在增加，这也可能与超声心动图的更常见的诊断有关。PH值也被认为是间质性肺病患者死亡率增加的一个指标。在达纳角举行的第四届世卫组织会议更新了重度PH的病理生物学概念，但到目前为止还没有找到根治方法。越来越多的人认识到血管增生性病变中的细胞具有抗凋亡作用，近年来关于骨髓来源的前体细胞在血管重塑中的作用已经有了大量的信息，但BM来源的前体细胞是否参与了PAH血管增生性病变的发展还没有得到研究。本课题组已经建立了SU5416/慢性缺氧(SuHx)模型，作为严重血管增生性PAH的模型。我们的中心假设是，骨髓来源的前体细胞是重要的，并通过生长因子的产生和植入血管壁来促进血管增生性病变的发展。我们的初步数据表明，在SuHx动物的小肺动脉内及其周围存在多能细胞。在拟议的实验过程中，我们将建立各种技术，包括骨髓重建和FACS分析，作为工具来阐明骨髓来源的前体细胞在严重实验性PAH血管增生性病变发展中的作用。BM来源的前体细胞对PAH的血管增殖有重要作用的假设将在两个特定的目标中得到验证：在特定的目标1中，我们将回答BM来源的前体细胞在血管增生性病变和血液中是否增加的问题，并显示在严重的血管增生性PAH中生长因子的产生增加。在特定的目标2中，我们将研究严重血管增生性PAH中BM来源的前体细胞重新聚集到肺血管系统的机制。我们将专门研究抑制凋亡和阻断CXCR4是否会减少前体细胞归巢、血管增殖和PH。总之，本项目旨在证明骨髓来源的前体细胞通过产生生长因子和植入血管壁来促进PAH中的血管增殖。 公共卫生相关性：在这项提案中，我们将调查骨髓来源的前体细胞是否参与血管增生性肺动脉高压的发生。这一问题具有很高的翻译相关性，因为目前还没有针对血管增生性PH和前体细胞的根治性治疗方法，目前已经对PH的治疗进行了研究，但并不了解骨髓来源的前体细胞在肺动脉血管增殖中的作用。通过揭示骨髓源性前体细胞的作用机制，如局部植入或血管生成生长因子的产生，抑制前体细胞的归巢或使用转基因前体细胞作为特定治疗的载体，可能会产生新的治疗选择。

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. PUBLIC HEALTH RELEVANCE: In this proposal, we will investigate the question, whether bone marrow-derived precursor cells participate in the development of angioproliferative pulmonary arterial hypertension. This question of high translational relevance, as there is currently no curative therapy for angioproliferative PH and precursor cells are already currently investigated for therapy of PH without an understanding of the contribution of bone marrow-derived precursor cells to pulmonary arterial angioproliferation. By uncovering the mechanisms, such as local engraftment or production of angiogenic growth factors, which underlie the contribution of bone marrow- derived precursor cells, new therapeutic options may arise from inhibiting the homing of precursor cells or from using genetically modified precursor cells as vehicles for specific therapy.