Ceramide-induced lung destruction in emphysema

描述（申请人提供）：肺气肿是一种常见的肺部疾病，没有有效的治疗方法。其独特的特征是肺组织的最终消失和肺泡毛细血管单位的丧失。即使在戒烟后很长一段时间，肺的损害仍是持续和进行性的。直到最近，研究（例如，通过抑制血管内皮生长因子受体，VEGFR-inh）发现了细胞凋亡在肺气肿发病过程中的关键作用，与氧化应激和基质蛋白酶激活一起，所有这些协同作用，引发肺泡破坏。开发肺气肿患者治疗的关键是确定触发、放大和维持肺泡细胞破坏的分子机制。神经酰胺是神经鞘脂的一种信号传导物质，是不同器官细胞凋亡的重要介质。我们最近在小鼠和大鼠建立的VEGFR- inh肺气肿模型中证明神经酰胺是肺细胞凋亡和肺气肿的关键介质。此外，我们开发了先进的方法来量化神经酰胺及其脂肪酸谱，并报告了其不同分子种类在肺气肿患者肺中的显著增加。结合神经酰胺与氧化应激和蛋白酶诱导相关的证据，这些数据坚定地表明神经酰胺是与肺气肿发病相关的多个过程的新型和潜在关键介质。因此，我们假设一种不平衡的、上调的神经酰胺信号触发机制导致并放大肺气肿中的肺泡破坏。这些机制被称为“破坏性途径”，包括肺细胞凋亡、氧化应激和基质蛋白水解。在Specific Aim (SA) #1中，我们将研究神经酰胺上调是否必要和足以引发肺气肿。我们将利用VEGFR-inh模型，通过药理学和分子（酸性鞘磷脂酶和丝氨酸-棕榈酰转移酶SiRNA）策略抑制神经酰胺。在SA #2中，我们将确定神经酰胺自我放大其合成的机制，从而进一步触发旁分泌水平的肺泡破坏放大。最后，SA #3将提出，恢复促凋亡神经酰胺与促生存鞘鞘醇-1- p的鞘脂信号传导平衡将阻止肺泡凋亡，从而导致肺气肿。一旦了解，神经酰胺的分子失调可以提供治疗和/或预防肺气肿的靶点。

DESCRIPTION (provided by applicant): Pulmonary emphysema is a prevalent lung disease with no effective treatment. Its unique features are the ultimate disappearance of lung tissue and loss of alveoler-capillary units. The lung destruction becomes sustained and progressive even long after discontinuation of smoking. Only recently, investigations (e.g., via inhibition of vascular endothelial growth factor receptor, VEGFR-inh) have uncovered a critical role for apoptosis in emphysema pathogenesis, in conjunction with oxidative stress and matrix protease activation, all of which synergize, triggering alveolar destruction. Key to developing treatments for emphysema patients is identifying the molecular mechanisms that trigger, amplify, and sustain alveolar cell destruction. Ceramide, a signaling sphingolipid, is now known to be a critical mediator of apoptosis in different organs. We recently demonstrated that ceramide is a key mediator of lung apoptosis and emphysema in the established VEGFR- inh model of emphysema in both mice and rats. Moreover, we developed cutting-edge approaches to quantify ceramide and its fatty acid profile and report striking increases in its different molecular species in the lungs of emphysema patients. Together with evidence linking ceramide with oxidative stress and protease induction, these data firmly position ceramide as a novel and potentially key mediator of multiple processes linked to emphysema pathogenesis. Therefore, we hypothesize that an imbalanced, upregulated ceramide signaling triggers mechanisms that cause and amplify the alveolar destruction in emphysema. These mechanisms, hereby named "destructive pathways", involve lung cell apoptosis, oxidative stress, and matrix proteolysis. In Specific Aim (SA) #1 we will investigate whether ceramide upregulation is necessary and sufficient to trigger emphysema. We will utilize the VEGFR-inh model and inhibit ceramide by pharmacologic, and molecular (acid sphingomyelinase and serine-palmitoyl transferase SiRNA) strategies. In SA #2 we will identify the mechanisms by which ceramide self-amplifies its synthesis, thereby triggering a further, paracrine level of amplification of alveolar destruction. Finally, SA #3 will propose that restoring the balance of sphingolipid signaling of the pro-apoptotic ceramide vs. pro-survival sphingosine-1-P will block alveolar apoptosis and thus emphysema. Once understood, the molecular dis-regulation of ceramide could offer a target for treatments and/or prevention of emphysema.