Identification of vascular-derived signals for alveolar lung repair

识别肺泡肺修复的血管源信号

基本信息

批准号：
8856658
负责人：
Shahin Rafii
金额：
$ 58.82万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8856658
关键词：
Adult Alveolar Bleomycin Blood Blood Platelets Blood Vessels Blood capillaries CXCL12 gene CXCR4 Receptors CXCR4 gene Capillary Endothelial Cell Cell Line Cells Chemicals Cicatrix Clinic Clinical Data Deposition Development Embryonic Development Endothelial Cells Endothelium Engineering Engraftment Epidermal Growth Factor Receptor Excision FGFR1 gene Fibrosis Gases Goals Growth Factor Health Hematopoietic Human Hyperoxia Infusion procedures Injury Lead Left Ligands Liver Lung Lung Transplantation Lung diseases Malignant Neoplasms Marrow Mediating Metalloproteases Methods Modeling Mus Myeloid Cells Natural regeneration Nutrient Organ Organogenesis Oxygen Pathway interactions Patients Phenocopy Plasma Play Pneumonectomy Production Quality of life Recombinants Recruitment Activity Respiration Disorders Respiratory physiology Role Signal Transduction Staging Stromal Cell-Derived Factor 1 Structure of parenchyma of lung Surface Technology Testing Therapeutic Tissues Toxin Translations Transplantation Trauma Up-Regulation Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors base capillary chemotherapeutic agent chemotherapy cigarette smoking defined contribution design human MMP14 protein improved in vivo injured knock-down lung injury lung regeneration lung repair novel novel strategies novel therapeutic intervention pre-clinical prevent programs pulmonary function receptor regenerative repaired research study tool

项目摘要

DESCRIPTION (provided by applicant): Current therapeutic approaches for the repair of the injured lung tissue have had no major long-term benefit in restoring pulmonary function. We have set forth the concept that pulmonary capillary endothelial cells (PCECs) are not just passive conduits that deliver oxygen and nutrients but rather by establishing a supportive niche play a key role in lung regeneration and repair. The overarching goal of this project is to define the mechanism by which after lung injury, activated PCECs through production of growth factors, defined as angiocrine factors, support alveolar regeneration without provoking aberrant fibrosis. We have established the phenotypic definition of PCECs and have shown that after left lung pneumonectomy (PNX), activation of the VEGF-A receptor-2 (VEGFR2) and FGFR1 expressed on the PCECs leads to upregulation of the metalloproteinase MMP14. MMP14 via unmasking cryptic EGF-receptor ligand domains stimulate alveolar regeneration. Notably, transplantation and engraftment of wild-type PCECs expressing MMP14 into the lung of VEGFR2/FGFR1 deficient mice restores lung alveolarization without stimulating fibrosis. However, the mechanism by which PNX activates PCECs to produce angiocrine factors is unknown. Our preliminary data indicate that after PNX, hyperoxia and bleomycin-induced lung injury, myeloid cells and platelets are recruited to the injured lung tissue and by deposition of VEGF-A and stromal derived factor-1 (SDF- 1, CXCl12) activate their cognate receptors VEGFR2 and CXCR4 expressed on PCECs to produce angiocrine factors initiating lung repair. Based on these data, we hypothesize that after lung injury, hematopoietic cells are recruited to pulmonary capillary vessels and by deploying VEGF-A and SDF-1 stimulate VEGFR2+CXCR4+ PCECs to produce alveolar-active angiocrine factors that support lung repair, while preventing aberrant fibrosis. We plan to leverage lung injury models and technologies developed in our lab, including a new approach to reprogram amniotic cells into vascular endothelial cells (rAC-VECs) to execute the following experiments: Aim 1. Dissect the mechanism by which activation of CXCR4 in VEGFR2+ PCECs elicits and maintains angiocrine-mediated lung repair. Aim 2. Examine the role of recruited hematopoietic cells to damaged lung vessels in mediating PCEC activation, angiocrine factor production and lung repair while preventing aberrant fibrosis. Aim 3. Determine the role of reciprocal crosstalk between hematopoietic cells and PCECs in inducing angiocrine signaling and accelerating alveolar regeneration and repair. Our proposed experiments will set the stage for development of pre-clinical strategies in which by proper activation of PCECs or transplantation of lung-specific engineered PCECs will allow for stimulating lung repair, thus improving respiratory functions and minimizing maladaptive remodeling into fibrotic tissues.

描述（由申请人提供）：目前修复受损肺组织的治疗方法在恢复肺功能方面没有重大的长期益处。我们提出了这样的概念：肺毛细血管内皮细胞（PCEC）不仅仅是输送氧气和营养物质的被动导管，而且通过建立支持性生态位在肺再生和修复中发挥关键作用。该项目的总体目标是确定肺损伤后通过产生生长因子（定义为血管分泌因子）激活 PCEC 的机制，支持肺泡再生而不引发异常纤维化。我们已经建立了 PCEC 的表型定义，并表明在左肺全肺切除术 (PNX) 后，PCEC 上表达的 VEGF-A 受体 2 (VEGFR2) 和 FGFR1 的激活导致金属蛋白酶 MMP14 上调。 MMP14 通过揭开神秘的 EGF 受体配体结构域来刺激肺泡再生。值得注意的是，将表达 MMP14 的野生型 PCEC 移植和植入 VEGFR2/FGFR1 缺陷小鼠的肺中可以恢复肺泡化，而不会刺激纤维化。然而，PNX 激活 PCEC 产生血管分泌因子的机制尚不清楚。我们的初步数据表明，在 PNX、高氧和博来霉素诱导的肺损伤后，骨髓细胞和血小板被募集到受损的肺组织，并通过 VEGF-A 和基质衍生因子 1（SDF-1、CXCl12）的沉积激活其同源细胞。 PCEC 上表达的受体 VEGFR2 和 CXCR4 可产生启动肺修复的血管分泌因子。基于这些数据，我们假设肺损伤后，造血细胞被募集到肺毛细血管，并通过部署 VEGF-A 和 SDF-1 刺激 VEGFR2+CXCR4+ PCEC 产生肺泡活性血管分泌因子，支持肺修复，同时防止异常。纤维化。我们计划利用我们实验室开发的肺损伤模型和技术，包括将羊膜细胞重编程为血管内皮细胞 (rAC-VEC) 的新方法来执行以下实验：目标 1. 剖析 VEGFR2+ 中 CXCR4 激活的机制PCEC 引发并维持血管分泌介导的肺修复。目标 2. 检查向受损肺血管募集的造血细胞在介导 PCEC 激活、血管分泌因子产生和肺修复同时防止异常纤维化中的作用。目标3。确定造血细胞和 PCEC 之间的相互串扰在诱导血管分泌信号传导和加速肺泡再生和修复中的作用。我们提出的实验将为临床前策略的开发奠定基础，通过适当激活 PCEC 或移植肺部特异性工程化 PCEC，将刺激肺部修复，从而改善呼吸功能并最大限度地减少纤维化组织的适应不良重塑。