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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要这是一项为期 18 个月的研究计划，将使申请人能够在以下领域开展学术研究生涯：肺科医学。申请人目前是肺科学和重症监护医学的研究员科罗拉多大学/国家犹太健康中心。 Irina Petrache 博士是一位知名的医学科学家肺气肿、肺损伤和修复、肺血管生物学和鞘脂信号传导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，一位在肺先天性方面拥有专业知识的医学科学家免疫反应、单核细胞-内皮相互作用和 α1 抗胰蛋白酶缺乏将成为辅助因素。拟议的研究将调查慢性吸烟（CS）损害的机制人肺微血管内皮细胞（HLMVEC）经历适当的稳态和应激的能力诱导自噬（生存和修复过程）并进行血管生成（损伤修复所需）。该机制具有重要的临床意义，因为 HLMVEC 是肺泡细胞的重要组成部分。气体交换、宿主防御和损伤修复所需的膜。应用的科学前提依靠 S1P 受体 1 (S1P1) 的 1 磷酸鞘氨醇 (S1P) 信号传导的关键作用来确保 LMVEC 生存、增殖和屏障功能。来自主要申办者的可靠已发表的初步数据实验室表明增强 S1P-S1P1 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存活和功能的影响尚未确定。被定义。申请人假设 HLMVEC 在慢性 CS 后发生适应不良变化暴露，其特征是由于 S1P1 信号传导减弱而导致自噬受损和血管生成减弱，这可以通过增强 S1P-S1P1 信令来逆转。申请人将进行初级隔离和培养 HLMVEC 来自具有慢性吸烟史或终生不吸烟者的未识别人类供体肺部并研究基线 S1P-S1P1 信号传导的差异及其修复反应的质量（自噬和管形成（血管生成的替代））以适应稳态和应激条件。最后，她会决定这些功能对完整的 S1P-S1P1 信号传导的依赖性，通过酶功能的获得和丧失，受体。拟议的项目将是定义慢性病具体而新颖的机制的重要一步。 CS 引起的 LMVEC 损伤和功能障碍，因此可能为治疗方法的开发提供信息继发于慢性阻塞性肺病（COPD）的破坏性疾病，例如肺气肿和肺动脉高压。申请人将学习大量的转化研究技能，并计划使用拟议项目的结果该项目将构成她作为独立研究员未来研究资助的基础，包括 K08 奖。申请人得到了她的导师、她的研究咨询委员会和该部门的大力支持。