Signal transduction mechanisms that mediate normal and pathologic angiogenesis

描述（由申请人提供）：支气管肺发育不良（BPD）是一种常见疾病，影响接受机械通气和氧疗的早产儿。在美国，每年有超过500，000名婴儿早产，其中约49，000名是BPD患者。BPD的病理学与肺发育的“停滞”一致，其特征在于血管生成和肺泡化受损。重要的是，BPD患者的肺发育缺陷导致成年后肺功能持续受损，导致肺动脉高压（PAH）和慢性阻塞性肺病（COPD）。BPD的发病机制尚不清楚，目前的治疗方法效果不佳。本提案的目标包括：1.揭示高氧处理小鼠（BPD小鼠模型）发病机制的新机制。2.为高氧治疗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（GIT 1）基因敲除（ecGIT 1-KO）小鼠和高氧处理小鼠都具有类似BPD的特征，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，在两种模型的肺中存在增强的Delta样4（Dll 4）介导的Notch信号传导。Notch信号传导是严格依赖于细胞类型和环境的。我们的研究结果还表明，Dll 4激活EC中的Notch 4以抑制血管生成，而Dll 4激活气道上皮细胞（AEC）中的Notch 1以通过EC-EC和EC-AEC串扰抑制肺泡化。这些抑制作用可能通过降低细胞增殖和细胞存活而发生。基于这些令人兴奋的发现，我们假设增强的Dll 4介导的Notch信号传导有助于BPD中的血管生成和肺泡化，如通过ecGIT 1-KO小鼠和高氧处理的小鼠所建模的。为了验证我们的假设，提出了三个目标。目的1：研究Dll 4介导的Notch信号通路在ecGIT 1-KO小鼠EC-EC和EC-AEC串扰中的作用及机制。目的2：研究Dll 4介导的Notch 1/4信号通路在高氧处理小鼠中的作用。目的3：评价抑制Dll 4对高氧小鼠肺发育的影响。实现该建议的目的将填补有关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。我们还打算发现BPD和相关肺部疾病（如COPD和PAH）的新治疗策略。从广义上讲，这些结果将提供对正常和病理性血管生成机制的深入了解，这些机制在癌症、糖尿病、缺血性心脏和脑血管疾病中可能是重要的。

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.