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最终消失，肺泡毛细血管单位丢失。即使在戒烟很长一段时间后，肺的破坏也会持续和进展。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，所有这些都协同作用，触发肺泡破坏。开发肺气肿患者治疗方法的关键是确定触发、放大和维持肺泡细胞破坏的分子机制。神经酰胺是一种信号转导鞘磷脂，现在被认为是不同器官中细胞凋亡的关键介质。我们最近在建立的小鼠和大鼠肺气肿VEGFR-INH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，我们开发了尖端方法来量化神经酰胺及其脂肪酸分布，并报告了肺气肿患者肺中神经酰胺不同分子种类的显著增加。结合将神经酰胺与氧化应激和蛋白酶诱导联系在一起的证据，这些数据坚定地将神经酰胺定位为一种新的、潜在的与肺气肿发病相关的多个过程的关键介质。因此，我们假设，不平衡的、上调的神经酰胺信号触发了导致和放大肺气肿肺泡破坏的机制。这些机制被称为“破坏性途径”，涉及肺细胞凋亡、氧化应激和基质蛋白分解。在特定目的(SA)#1中，我们将调查神经酰胺上调是否是触发肺气肿的必要条件和充分条件。我们将利用VEGFR-inh模型，通过药物和分子(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，从而触发进一步的旁分泌水平的肺泡破坏。最后，SA#3将提出，恢复支持凋亡的神经酰胺与支持生存的神经鞘氨醇-1-P之间的鞘磷脂信号平衡将阻止肺泡细胞凋亡，从而阻止肺气肿。一旦了解，神经酰胺的分子失调可能为肺气肿的治疗和/或预防提供靶点。

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.