EMAP II: Pulmonary Vascular Mediator

EMAP II：肺血管介质

• 批准号: 8765229
• 负责人: Margaret A Schwarz
• 金额: $ 41.55万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8765229
• 关键词: Ablation; Alveolar; Angiogenesis Inhibition; Angiogenic Proteins; Animal Model; Antibodies; Binding; Blocking Antibodies; Blood Vessels; Blood capillaries; Bronchopulmonary Dysplasia; Cell Adhesion; Cells; Clinical; Data; Development; Distal; Endothelial Cells; Epithelial; Epithelium; Functional disorder; Glucocorticoids; Growth; Human; Hyperoxia; Integrins; Lead; Link; Lung; Measurable; Mediating; Mediator of activation protein; Modeling; Morphogenesis; Mus; Pharmaceutical Preparations; Phenocopy; Premature Birth; Premature Infant; Process; Prognostic Marker; Property; Pulmonary Fibrosis; Receptor Signaling; Risk Factors; Role; Signal Transduction; Source; TNF gene; Therapeutic; Transgenic Mice; Treatment Efficacy; Ubiquitin; Ubiquitination; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascularization; Ventilator; Work; aerosolized; angiogenesis; capillary; design; endothelial monocyte-activating polypeptide II; gain of function; loss of function; macrophage; migration; monocyte; novel therapeutics; overexpression; polypeptide; prevent; receptor; response; surfactant; vascular inflammation

DESCRIPTION (provided by applicant): Angiogenesis is an essential process in pulmonary morphogenesis. Vascular disruption can lead to alveolar abnormalities that are often fatal, such as Bronchopulmonary Dysplasia (BPD) found in premature infants. BPD studies in humans and animal models demonstrate a direct link between lung hypoplasia and impaired expression and signaling of the essential vascular mediator Vascular Endothelial Growth Factor (VEGF) and its receptors (VEGFR). Therapy using VEGF monotherapy is insufficient to rescue lung morphogenesis, as downstream VEGF signaling remains disrupted. Identifying regulators of VEGFR signaling is crucial to develop new therapeutic strategies for BPD. We recently made numerous discoveries indicating that the potent anti-angiogenic protein and proinflammatory mediator Endothelial-Monocyte Activating Polypeptide (EMAP) II functions as a likely director of pulmonary vascular formation in the developing lung as: A) its pulmonary expression is inversely correlated to periods of vascularization, B) our preliminary data indicates that EMAP II expression is markedly elevated in pulmonary epithelium and macrophages in human and animal models of BPD, and C) delivery of exogenous EMAP II profoundly disrupts alveolar-capillary growth while our preliminary data indicates that an EMAP II function blocking antibody rescues distal alveolar growth. Mechanistically, we demonstrated that EMAP II inhibits endothelial cell adhesion via ¿5¿1 integrin, and blocks vascular endothelial growth factor receptor II (VEGFR2) signaling. Although the mechanism by which EMAP II regulates VEGFR2 signaling is unknown, recent work suggests that EMAP II modulates the TGF receptor by targeting it for ubiquitination and degradation via SMURF2 (Smad specific ubiquitin regulatory factor 2). In addition to EMAP II's anti-angiogenic properties, EMAP II also promotes proinflammatory responses via stimulation of macrophage migration and TNF¿ secretion. We hypothesize that elevated expression of EMAP II in BPD results in inhibition of vascular development through a SMURF2 / VEGFR2 dependent manner that results in suppression of distal alveolar development. Our specific aims are to: 1) determine the contribution of epithelial and macrophage EMAP II to vascular inhibition in BPD; 2) determine if EMAP II anti-angiogenic inhibition is a VEGFR2 / SMURF2 mediated mechanism; and 3) determine therapeutic potential for aerosolized delivery of an EMAP II function blocking antibody in rescuing blood vessel formation in BPD. Successful accomplishment of our specific aims will establish the scientific evidence supporting EMAP II's role in BPD and allow design of a multi-drug therapeutic approach that will enhance pulmonary vascularization. Furthermore, EMAP II's marked elevation in BPD may identify its expression as a measurable risk factor allowing it to serve as a prognostic indicator in premature infants.

描述(申请人提供)：血管生成是肺形态发生中的一个基本过程。血管破裂可导致肺泡异常，通常是致命的，如早产儿发现的支气管肺发育不良(BPD)。BPD在人和动物模型上的研究表明，肺发育不良与基本血管介质血管内皮生长因子(VEGFR)及其受体(VEGFR)的表达和信号受损直接相关。使用血管内皮生长因子单一疗法不足以挽救肺形态发生，因为下游血管内皮生长因子信号仍然中断。确定VEGFR信号调节因子对于开发BPD的新治疗策略至关重要。我们最近的大量发现表明，有效的抗血管生成蛋白和促炎介质内皮单核细胞激活多肽(EMAP II)在发育中的肺组织中可能作为肺血管形成的导向因子发挥作用，因为：A)它的肺表达与血管形成时间呈负相关，B)我们的初步数据表明，在BPD的人和动物模型中，EMAP II在肺上皮和巨噬细胞中的表达显著增加，C)外源性EMAP II的输送深刻地破坏了肺泡-毛细血管的生长，而我们的初步数据表明，EMAP II功能阻断抗体挽救了远端肺泡的生长。从机制上讲，我们证明了EMAP II通过整合素抑制内皮细胞黏附，并阻断血管内皮生长因子受体II(VEGFR2)信号转导。尽管EMAP II调节VEGFR2信号的机制尚不清楚，但最近的研究表明，EMAP II通过SMURF2(Smad特异性泛素调节因子2)靶向泛素化和降解来调节转化生长因子受体。除了EMAP II的抗血管生成特性外，EMAP II还通过刺激巨噬细胞迁移和分泌肿瘤坏死因子来促进促炎反应。我们假设在BPD中EMAP II的高表达通过SMURF2/VEGFR2依赖的方式导致血管发育抑制，从而导致远端肺泡发育的抑制。我们的具体目标是：1)确定上皮和巨噬细胞EMAP II在BPD血管抑制中的作用；2)确定EMAP II抗血管生成抑制是否是VEGFR2/SMURF2介导的机制；以及3)确定雾化递送EMAP II功能阻断抗体在拯救BPD血管形成中的治疗潜力。我们的特定目标的成功实现将建立支持EMAP II在BPD中的作用的科学证据，并允许设计一种将增强肺血管形成的多种药物治疗方法。此外，EMAP II在BPD中的显著升高可能会将其表达确定为一个可测量的危险因素，从而使其成为早产儿的预后指标。