Effect of chronic cigarette smoking on human microvascular endothelial cell metabolism and function

长期吸烟对人微血管内皮细胞代谢及功能的影响

• 批准号: 10231734
• 负责人: Khushboo Goel
• 金额: $ 7.49万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231734
• 关键词: Acute; Address; Advisory Committees; Alveolar; Apoptosis; Apoptotic; Autophagocytosis; Award; Biology; Blood Circulation; Blood Vessels; Blood capillaries; Cause of Death; Cell Death; Cell Line; Cell Survival; Cell membrane; Cell physiology; Cells; Cellular Metabolic Process; Ceramides; Cessation of life; Chronic; Chronic Obstructive Airway Disease; Clinical; Colorado; Critical Care; Data; Dependence; Development; Disease; Endothelial Cells; Endothelium; Energy Metabolism; Ensure; Environment; Enzymes; Epithelial; Epithelial Cells; Equilibrium; Exposure to; Functional disorder; G-Protein-Coupled Receptors; Gases; Health; Host Defense; Human; Impairment; Inflammation; Inhalation; Injury; Innate Immune Response; Knowledge; Laboratories; Lead; Learning; Life; Literature; Lung; Mediating; Medicine; Membrane; Mentors; Metabolic; Morbidity - disease rate; Mus; Pathogenesis; Pathology; Patients; Perfusion; Phenotype; Physicians; Price; Process; Proliferating; Publishing; Pulmonary Emphysema; Pulmonary Hypertension; Pulmonology; Recording of previous events; Recycling; Research; Research Personnel; Research Project Grants; Research Proposals; Role; Science; Scientist; Secondary to; Signal Pathway; Signal Transduction; Smoker; Smoking; Sphingolipids; Sphingosine-1-Phosphate Receptor; Stress; Structure; Surface; Testing; Translational Research; Tube; United States; Universities; Vascular remodeling; alpha 1-Antitrypsin Deficiency; alveolar epithelium; angiogenesis; career; career development; cell injury; cigarette smoking; follower of religion Jewish; improved; injury and repair; loss of function; lung injury; monocyte; mortality; non-smoker; novel; novel therapeutic intervention; protective effect; receptor; repair function; repaired; reparative process; response; skills; small molecule; smoking exposure; smoking-related lung disease; sphingosine 1-phosphate; targeted treatment; therapy development; vascular bed; ventilation

PROJECT SUMMARY/ABSTRACT This is an 18-month research proposal which will allow the applicant to develop an academic research career in Pulmonary Medicine. The applicant is currently a fellow in Pulmonary Sciences and Critical Care Medicine at the University of Colorado/National Jewish Health. Dr. Irina Petrache, an established physician-scientist with expertise in emphysema, lung injury and repair, lung vascular biology, and sphingolipid signaling, will be the applicant's primary mentor and sponsor. Dr. Karina Serban, a physician scientist with expertise in lung innate immune responses, monocyte-endothelial interactions, and alpha 1 antitrypsin deficiency, will be the co-mentor. The proposed research will investigate the mechanisms by which chronic cigarette smoking (CS) impairs the ability of human lung microvascular endothelial cells (HLMVEC) to undergo proper homeostatic and stress- induced autophagy (a survival and reparative process) and perform angiogenesis (required for injury repair). This mechanism has significant clinical implications, since HLMVEC are essential components of the alveolar membrane required for gas exchange, host defense, and injury repair. The scientific premise of the application relies on the key role of sphingosine-1 phosphate (S1P) signaling via S1P receptor 1 (S1P1) to ensure LMVEC survival, proliferation, and barrier function. Robust published and preliminary data from the primary sponsor's laboratory show that augmenting the S1P-S1P1 signaling pathway protects LMVECs from the detrimental effects of acute CS exposure. However, the effect of chronic CS exposure on LMVEC survival and function has not yet been defined. The applicant hypothesizes that HLMVEC develop maladaptive changes following chronic CS exposure, characterized by impaired autophagy and weakened angiogenesis due to diminished S1P1 signaling, which can be reversed by augmenting S1P-S1P1 signaling. The applicant will isolate and culture primary HLMVEC from de-identified human donor lungs with a history of chronic smoking or from lifelong nonsmokers and study differences in baseline S1P-S1P1 signaling and the quality of their repair responses (autophagy and tube formation, a surrogate of angiogenesis) to homeostatic and stress conditions. Finally, she will determine the dependency of these functions on intact S1P-S1P1 signaling by gain and loss of function of enzymes and receptors. The proposed project will be an important step in defining a specific and novel mechanism of chronic CS-induced LMVEC injury and dysfunction, and therefore may inform the development of therapies to treat devastating diseases such as emphysema and pulmonary hypertension secondary to COPD. The applicant will learn a large array of translational research skills and plans to use the results from the proposed project will form the basis of her future research grants as an independent researcher, including the K08 award. The applicant has strong support from her mentors, her research advisory committee, and the Division.

项目总结/摘要 这是一个为期18个月的研究计划，将允许申请人在以下领域发展学术研究生涯： 肺内科申请人目前是肺科学和重症监护医学研究员， 科罗拉多大学/国家犹太健康。Irina Petrache博士，一位著名的医学科学家， 在肺气肿，肺损伤和修复，肺血管生物学和鞘脂信号方面的专业知识，将是 申请人的主要导师和担保人。Karina Serban博士，一位在先天性肺疾病方面具有专长的内科科学家， 免疫反应、单核细胞-内皮细胞相互作用和α 1抗胰蛋白酶缺乏将是共同指导者。 这项拟议中的研究将探讨慢性吸烟（CS）损害神经功能的机制。 人肺微血管内皮细胞（HLMVEC）承受适当稳态和应激的能力- 诱导自噬（存活和修复过程）并进行血管生成（损伤修复所需）。 这一机制具有重要的临床意义，因为HLMVEC是肺泡上皮细胞的重要组成部分， 膜需要气体交换，宿主防御和损伤修复。申请的科学前提 依赖于鞘氨醇-1磷酸（S1 P）信号通过S1 P受体1（S1 P1）的关键作用，以确保LMVEC 存活、增殖和屏障功能。来自主要申办者的稳健的已发表和初步数据 实验表明，增强S1 P-S1 P1信号通路可保护LMVEC免受有害影响， 急性CS暴露。然而，慢性CS暴露对LMVEC存活和功能的影响还没有 被定义。申请方假设HLMVEC在慢性CS后发生适应不良变化 暴露，其特征在于由于S1 P1信号传导减少而导致的自噬受损和血管生成减弱， 这可以通过增加S1 P-S1 P1信号来逆转。申请人将分离和培养原代 HLMVEC来自具有慢性吸烟史或终身不吸烟者的未识别人类供体肺 并研究基线S1 P-S1 P1信号传导及其修复反应的质量（自噬和 管形成，血管生成的替代物）到稳态和应激条件。最后，她将决定 这些功能依赖于完整的S1 P-S1 P1信号传导，通过酶功能的获得和丧失， 受体。拟议的项目将是确定慢性炎症的具体和新机制的重要一步。 CS诱导的LMVEC损伤和功能障碍，因此可以为治疗 慢性阻塞性肺病（COPD）继发的肺气肿和肺动脉高压等严重疾病。 申请人将学习大量的转化研究技能，并计划使用拟议的 该项目将成为她未来作为独立研究人员的研究赠款的基础，包括K 08奖。 申请人得到了她的导师，她的研究咨询委员会和该司的大力支持。