Control of Angiogenesis in neonatal Hyperoxic Lung Injury

新生儿高氧性肺损伤中血管生成的控制

• 批准号: 8292190
• 负责人: Heber C. Nielsen
• 金额: $ 19.88万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-05 至 2013-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292190
• 关键词: Accounting; Affect; Air; Alveolar; Angiostatins; Apoptosis; Asthma; Attention; Automobile Driving; Binding; Blocking Antibodies; Bronchopulmonary Dysplasia; Cell Death; Cell Proliferation; Child health care; Childhood; Childhood Asthma; Chronic lung disease; Data; Development; Endothelial Cells; Epithelial Cells; Epitopes; Equilibrium; Family; Flow Cytometry; Foundations; Gelatinase B; Gene Expression; Genetic Transcription; Goals; Health; Health Care Costs; Healthcare; Hyperoxia; Immunohistochemistry; In Vitro; Injury; Knowledge; Kringles; Lead; Lung; Measures; Microcirculatory Bed; Modeling; Molecular; Mus; Neonatal; Oxygen; Pathogenesis; Pathway interactions; Peptides; Plasminogen; Play; Premature Infant; Prevention approach; Process; Production; Proteins; Proteolysis; Regulation; Research; Role; Signal Transduction; Small Interfering RNA; Solid; Source; Testing; Tube; Type II Epithelial Receptor Cell; VEGFA gene; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascularization; Work; alveolar epithelium; angiogenesis; base; cell motility; cytokine; in vivo; injured; innovation; insight; lung development; lung injury; morphometry; neonatal lung injury; novel; novel strategies; novel therapeutics; pigment epithelium-derived factor; pigment epithelium-derived factor receptor; preterm lung injury; prevent; programs; promoter; protein expression; receptor; research study; response to injury

DESCRIPTION (provided by applicant): Bronchopulmonary Dysplasia, (BPD) is a significant health problem, accounting for $4 Billion in annual health care costs. This is second only to asthma in child health care costs. A major gap in understanding the pathogenesis of BPD is knowledge of interacting signals regulating the development of the alveolar unit (defined here as the alveolar epithelium and the underlying microvascular bed), and how these interacting signals are disrupted by hyperoxia. Our long term goal is to develop an understanding of the mechanisms of disrupted development of the alveolar unit in BPD. Our main objective is to develop mechanistic insight into normal and oxygen-injured development of the alveolar unit through study of angiostatic, using a candidate molecule approach. Our primary candidates are Pigment Epithelium Derived Factor (PEDF), and its upstream regulator Kringle 5 (K5). The processes of microvascularization and alveolarization are closely connected. Angiogenesis is closely regulated by a balance between pro- and anti-angiogenic signaling. Disruption of this balance by hyperoxia could cause abnormal development of alveolar units. We demonstrated that neonatal hyperoxic lung injury is associated with increased PEDF, particularly in alveolar crests, type II cells, and endothelial cells, while vascular endothelial growth factor (VEGF) is decreased. We will study the effect of PEDF induction or inhibition in vivo and in vitro on alveolarization and microvascularization, and study the mechanisms by which it inhibits angiogenesis. We hypothesize that hyperoxic injury in the neonatal lung disrupts the normal balance of angiogenic and angiostatic signaling, causing impaired microvascular development needed for proper alveolarization. We propose to study inhibition by PEDF of alveolarization and angiogenesis in neonatal mouse lungs and mouse lung endothelial cells. We will determine the mechanisms by which PEDF downregulates VEGF production and activity, and by which PEDF exerts its action. Finally, we will look upstream of PEDF at proximal angiostatins, particularly Kringle 5. Kringle 5 is produced by matrix metalloproteinase 9 (MMP-9) action, which we showed is significantly upregulated in neonatal lung oxygen injury and arrests alveologenesis. We will determine if angiostatic effects in hyperoxia are driven by a MMP-9 - K5 - PEDF pathway. These studies are innovative since they develop a new direction for studying mechanisms altering development of the alveolar unit in BPD. The impact of this proposal will be the development of a novel mechanistic pathway for BPD which could lead to new therapeutic strategies.

描述（由申请人提供）：支气管肺发育不良 (BPD) 是一个严重的健康问题，每年造成 40 亿美元的医疗保健费用。这在儿童医疗保健费用中仅次于哮喘。了解 BPD 发病机制的一个主要差距是了解调节肺泡单位（此处定义为肺泡上皮和下面的微血管床）发育的相互作用信号，以及这些相互作用信号如何被高氧破坏。我们的长期目标是了解 BPD 中肺泡单位发育紊乱的机制。我们的主要目标是通过使用候选分子方法研究血管抑制，深入了解肺泡单位的正常和氧损伤发育。我们的主要候选者是色素上皮衍生因子 (PEDF) 及其上游调节因子 Kringle 5 (K5)。微血管化和肺泡化的过程密切相关。血管生成受到促血管生成信号和抗血管生成信号之间的平衡的密切调节。高氧破坏这种平衡可能会导致肺泡单位发育异常。我们证明，新生儿高氧性肺损伤与 PEDF 增加有关，尤其是肺泡嵴、II 型细胞和内皮细胞中的 PEDF 增加，而血管内皮生长因子 (VEGF) 减少。我们将在体内外研究PEDF诱导或抑制对肺泡化和微血管化的影响，并研究其抑制血管生成的机制。我们假设新生儿肺的高氧损伤破坏了血管生成和血管抑制信号的正常平衡，导致适当肺泡化所需的微血管发育受损。我们建议研究 PEDF 对新生小鼠肺和小鼠肺内皮细胞中肺泡化和血管生成的抑制作用。我们将确定 PEDF 下调 VEGF 产生和活性的机制，以及 PEDF 发挥其作用的机制。最后，我们将关注 PEDF 上游的近端血管抑制素，特别是 Kringle 5。Kringle 5 由基质金属蛋白酶 9 (MMP-9) 作用产生，我们发现它在新生儿肺氧损伤中显着上调并阻止肺泡生成。我们将确定高氧条件下的血管抑制作用是否是由 MMP-9 - K5 - PEDF 途径驱动的。这些研究具有创新性，因为它们为研究改变 BPD 肺泡单位发育的机制开辟了新方向。该提案的影响将是开发一种新的 BPD 机制途径，这可能会带来新的治疗策略。