Signal transduction mechanisms that mediate normal and pathologic angiogenesis

描述(申请人提供)：支气管肺发育不良(BPD)是一种常见病，困扰着接受机械通气和氧疗的早产儿。在美国，每年有50多万名早产婴儿，其中约49,000名是BPD患者。BPD的病理与肺发育“停滞”相一致，其特征是血管生成和肺泡化受损。重要的是，BPD患者的肺发育缺陷会导致成年后持续的肺功能受损，导致肺动脉高压(PAH)和慢性阻塞性肺疾病(COPD)。BPD的潜在机制仍不清楚，目前的治疗方法并不有效。本研究的目的包括：1.揭示高氧处理小鼠(BPD小鼠模型)发病的新机制。2.为高氧处理小鼠提供新的治疗策略。由于内皮细胞特异性G蛋白偶联受体激酶2相互作用蛋白-1(GIT1)基因敲除小鼠和高氧处理小鼠与BPD相似，这两种小鼠模型是研究BPD发病机制的理想工具。我们的初步数据表明，在两种模型的肺中都存在增强的Delta like 4(DLL4)介导的Notch信号。Notch信令严格依赖于细胞类型和上下文。我们的发现还表明，DLL4激活EC中的Notch4以抑制血管生成，而DLL4激活气道上皮细胞(AEC)中的Notch1以通过EC-EC和EC-AEC串扰来抑制肺泡化。这些抑制作用可能是通过减少细胞增殖和细胞存活而发生的。基于这些令人兴奋的发现，我们假设增强的DLL4介导的Notch信号有助于ecGIT1-KO小鼠和高氧处理小鼠BPD的血管生成和肺泡化。为了验证我们的假设，我们提出了三个目标。目的1：探讨DLL4介导的Notch信号在ecGIT1-KO小鼠体内启动EC-EC和EC-AEC串扰的功能和机制。目的2：明确DLL4介导的Notch1/4信号在高氧处理小鼠中的作用。目的：评价抑制DLL4对高氧小鼠肺发育的治疗作用。完成该提案的目标将填补关于出生后肺发育机制和高氧相关肺功能障碍发病机制的具体知识空白。我们还打算为BPD和相关的肺部疾病，如COPD和PAH找到新的治疗策略。广泛地说，这些结果将提供对正常和病理性血管生成机制的洞察，这些机制可能在癌症、糖尿病、缺血性心脏和脑血管疾病中起重要作用。

DESCRIPTION (provided by applicant): Bronchopulmonary dysplasia (BPD) is a common disease afflicting premature newborns who receive mechanical ventilation and oxygen therapy. In the United States, there are more than 500,000 babies born prematurely each year, of which ~ 49,000 are BPD patients. The pathology of BPD is consistent with an "arrest" of lung development, characterized by impaired angiogenesis and alveolarization. Importantly, the defects of lung development in BPD patients cause persistent impaired lung function in adulthood, leading to pulmonary arterial hypertension (PAH) and chronic obstructive pulmonary disease (COPD). The underlying mechanisms of BPD are still unknown and the current therapy is not effective. The objectives of the current proposal include: 1. Reveal novel mechanisms of pathogenesis of hyperoxia treated mice (BPD mouse model). 2. Provide new therapeutic strategies of hyperoxia treated mice. Since both endothelial cell (EC) specific G protein-coupled receptor kinase 2-interacting protein-1 (GIT1) knockout (ecGIT1-KO) mice and hyperoxia treated mice resemble BPD, these two mouse models are ideal tools to study the mechanisms of BPD. Our preliminary data demonstrate that there is enhanced Delta like 4(Dll4) mediated Notch signaling in lungs of both models. Notch signaling is strictly cell type and context dependent. Our findings also imply that Dll4 activates Notch4 in EC to inhibit angiogenesis, while Dll4 activates Notch1 in airway epithelium cell (AEC) to inhibit alveolarization through EC-EC and EC-AEC crosstalk. These inhibitory effects possibly occur through decreased cell proliferation and cell survival. Based on these exciting findings, we hypothesize that enhanced Dll4 mediated Notch signaling contributes to the angiogenesis and alveolarization in BPD as modeled by ecGIT1-KO mice and hyperoxia treated mice. To test our hypothesis, three Aims are proposed. Aim 1: Determine the functions and mechanisms of EC-EC and EC-AEC crosstalk initiated by Dll4 mediated Notch signaling in ecGIT1-KO mice. Aim 2: Define Dll4 mediated Notch1/4 signaling in hyperoxia treated mice. Aim 3: Evaluate the therapeutic effects of inhibiting Dll4 on lung development of hyperoxia treated mice. Accomplishing the aims of the proposal will fill the specific knowledge gap regarding mechanisms of postnatal lung development and pathogenesis of hyperoxia related lung dysfunction. We also intend to discover novel therapeutic strategies for BPD and related lung diseases, such as COPD and PAH. Broadly, the results will provide insight into mechanisms of both normal and pathologic angiogenesis that may be important in cancer, diabetes, ischemic cardiac and cerebral vascular disease.