Identification of vascular-derived signals for alveolar lung repair

识别肺泡肺修复的血管源信号

• 批准号: 8708964
• 负责人: Shahin Rafii
• 金额: $ 58.52万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708964
• 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; Hematopoietic; Human; Hyperoxia; Infusion procedures; Injury; Lead; Left lung; 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; public health relevance; pulmonary function; receptor; regenerative; repaired; research study; tool

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）：目前用于修复损伤肺组织的治疗方法在恢复肺功能方面没有主要的长期益处。我们提出了肺毛细血管内皮细胞（PCECs）不仅仅是传递氧气和营养物质的被动通道，而是通过建立支持生态位在肺再生和修复中发挥关键作用的概念。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）激活的PCECs支持肺泡再生而不引起异常纤维化的机制。我们已经建立了PCECs的表型定义，并表明在左肺切除术（PNX）后，PCECs上表达的VEGF-A受体-2 （VEGFR2）和FGFR1的激活导致金属蛋白酶MMP14的上调。MMP14通过揭开隐藏的egf受体配体结构域刺激肺泡再生。值得注意的是，将表达MMP14的野生型PCECs移植和植入VEGFR2/FGFR1缺陷小鼠的肺中可以恢复肺泡化而不刺激纤维化。然而，PNX激活PCECs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、高氧和博莱霉素诱导的肺损伤后，髓细胞和血小板被募集到损伤的肺组织中，并通过VEGF-A和基质衍生因子-1 （SDF- 1、CXCl12）的沉积激活它们在PCECs上表达的同源受体VEGFR2和CXCR4，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，造血细胞被招募到肺毛细血管，并通过部署VEGF-A和SDF-1刺激VEGFR2+CXCR4+ PCECs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，包括一种将羊膜细胞重编程为血管内皮细胞（rAC-VECs）的新方法来执行以下实验：解析VEGFR2+ PCECs中CXCR4激活引发和维持血管分泌素介导的肺修复的机制。目标2。研究募集的造血细胞对受损肺血管在介导PCEC激活、血管分泌因子产生和肺修复中的作用，同时预防异常纤维化。目标3。