Cigarette smoke influences alveolar type II cell-derived exosomes

香烟烟雾影响肺泡 II 型细胞来源的外泌体

基本信息

批准号：
10164784
负责人：
Karim Bahmed
金额：
$ 19.71万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10164784
关键词：
Address Alveolar wall Apoptosis Applications Grants Blocking Antibodies Blood Circulation Cell Death Cell Separation Cells Characteristics Clinical Complex Cytoplasm DNA DNA Damage DNA Double Strand Break DNA Repair Data Development Disease Disease Progression Epithelial Extracellular Matrix Extracellular Space Failure Functional disorder Gene Expression Genomic DNA Goals Histones Human In Vitro Inflammatory Injury Lead Location Lung Matrix Metalloproteinases Membrane Mitochondria Mitochondrial DNA Mitochondrial Proteins Monoclonal Antibodies Mutation Nuclear Organ Donor Oxidative Stress Pathogenicity Pathologic Patients Proliferating Proteins Pulmonary Emphysema Pulmonary Surfactants RNA Reactive Oxygen Species Reporting Risk Factors Role Signal Transduction Therapeutic alveolar type II cell cell injury cigarette smoke cigarette smoke-induced cigarette smoking effective therapy environmental tobacco smoke exosome experience mitochondrial dysfunction novel therapeutic intervention oxidative damage repaired stem cells vesicular release

项目摘要

Abstract Alveolar type II (ATII) cells produce and secrete the pulmonary surfactant. They have stem cell potential, proliferate and restore the epithelium after damage. Emphysema is characterized by alveolar wall destruction. It is caused by cigarette smoking and second hand smoke. High oxidative stress induced by this exposure leads to ATII cell injury, mitochondrial and nuclear DNA damage. DNA double-strand breaks (DSBs) pose the most serious threat to the genomic and mitochondrial DNA. Mitochondrial DNA (mtDNA) is more susceptible to oxidative damage than nuclear DNA due to the lack of histones that serve as a barrier against damaging factors as well as limited DNA repair capacity. Failure to repair mtDNA DSBs can trigger a formation of mutations, deletions and mitophagy. Moreover, damaged mtDNA can be secreted from mitochondria to the cytoplasm and extracellular space via exosomes. Exosomes are small membrane vesicles that are released from the cell under normal or pathological conditions. They also serve as signaling vehicles by delivering proteins, DNA and RNA, to the recipient cells leading to alteration of their gene expression, proliferation, and differentiation. Furthermore, it has been reported that CD147 regulates complex I activity in mitochondria and cell apoptosis by interacting with mitochondrial proteins. CD147 is an extracellular matrix metalloproteinase (MMP) inducer and is known to stimulate MMPs expression. We detected high mtDNA and CD147 levels in ATII cell-derived exosomes obtained from patients with emphysema. We will use monoclonal antibody against CD147 to block its harmful function. Our hypothesis is tinhaetxmotsDoNmAesansdecCrDet1e4d7by ATII cells in emphysema induce injury in the recipient cells. Monoclonal antibody against CD147 will block circulation of exosomes with harmful content. In Specific Aim #1 we will determine the function of ATII cell-derived exosomes obtained from emphysema patients. We will study the role of exosomal mtDNA and CD147 on the recipient ATII cells. In Specific Aim #2, we will determine whether monoclonal antibody blocking CD147 will decrease the harmful function of exosomes on the recipient cultured ATII cells. Upon completion of the proposed study, we will have characterized the function of exosomes secreted by ATII cells in emphysema and their effect on the recipient cells. Monoclonal antibody against exosomal CD147 can provide a new therapeutic strategy against this disease progression.

抽象的牙槽II型（ATII）细胞产生并分泌肺表面活性剂。它们具有干细胞电位，损坏后增殖并恢复上皮。肺气肿的特征是肺泡壁破坏。它是由吸烟和二手烟引起的。这种暴露引起的高氧化应激导致为ATII细胞损伤，线粒体和核DNA损伤。 DNA双链断裂（DSB）构成最大对基因组和线粒体DNA的严重威胁。线粒体DNA（mtDNA）更易感由于缺乏作为障碍的障碍的组蛋白，氧化损伤比核DNA造成氧化损伤因素以及有限的DNA修复能力。无法修复mtDNA DSB会触发形成突变，缺失和线粒体。此外，受损的mtDNA可以从线粒体分泌到通过外泌体的细胞质和细胞外空间。外泌体是小膜囊泡在正常或病理条件下从细胞中释放。它们还通过将蛋白质，DNA和RNA传递到受体细胞，从而改变其基因表达，增殖和分化。此外，据报道CD147调节通过与线粒体蛋白相互作用，在线粒体和细胞凋亡中的复杂I活性。 CD147是细胞外基质金属蛋白酶（MMP）诱导剂，已知会刺激MMPS表达。我们在ATII细胞衍生的外泌体中检测到的高mtDNA和CD147水平气肿。我们将使用针对CD147的单克隆抗体来阻止其有害功能。我们的假设是 Tinhaetxmotsdonmaesansdeccrdet1e4d7by Atii细胞在肺气肿中诱导受体细胞损伤。单克隆抗体针对CD147将阻止具有有害含量的外泌体的循环。在特定的目标＃1中，我们将确定从肺气肿患者获得的ATII细胞衍生外泌体的功能。我们将研究外泌体的作用受体ATII细胞上的mtDNA和CD147。在特定的目标＃2中，我们将确定是否单克隆抗体阻止CD147将降低外泌体对受体培养的ATII细胞的有害功能。之上拟议研究的完成，我们将表征ATII细胞分泌的外泌体的功能肺气肿及其对受体细胞的影响。针对外泌体CD147的单克隆抗体可以提供针对这种疾病进展的新治疗策略。