Emphysema attenuation via modulation of macrophage NFKB and antiprotease activity

通过调节巨噬细胞 NFKB 和抗蛋白酶活性减轻肺气肿

• 批准号: 8294978
• 负责人: ANDREW A WILSON
• 金额: $ 12.96万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294978
• 关键词: Affect; Alveolar Macrophages; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Award; Biological; Biological Assay; Biology; Blood; Cell Count; Cells; Chronic; Cigarette smoke-induced emphysema; Clinical; Critical Care; Development; Disease; Educational process of instructing; Elastases; Environment; Epithelial; Exposure to; Foundations; Goals; Hereditary Disease; Human; Immunology; In Vitro; Inflammation; Inflammatory; Infusion procedures; Inherited; Injury; Kinetics; Knowledge; Lead; Lentivirus Vector; Leukocyte Elastase; Life; Liquid substance; Lung; Lung Inflammation; Lung diseases; Mentors; Methodology; Methods; Modeling; Molecular Biology; Monitor; Mus; NF-kappa B; Nuclear; Nuclear Translocation; Obstruction; Pathogenesis; Patient Care; Patients; Physicians; Physiological; Play; Principal Investigator; Protease Inhibitor; Proteins; Pulmonary Emphysema; Pulmonology; Research; Research Personnel; Resolution; Respiratory physiology; Risk; Role; Scientist; Signal Transduction; Subfamily lentivirinae; System; Testing; Therapeutic; Time; Wild Type Mouse; Work; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; attenuation; base; blood product; career; cell type; cellular transduction; cigarette smoke-induced; cigarette smoking; cytokine; gene therapy; healthy volunteer; in vivo; macrophage; novel; overexpression; p65; public health relevance; research study; response; skills; small hairpin RNA; symposium; tool; transcription factor

DESCRIPTION (provided by applicant): As a physician-scientist, my overarching career goal is to use the tools available to me in the research setting to work towards treatments for the lung diseases that I encounter in the clinical arena. I plan to become an independent principal investigator in an academic division of pulmonary medicine and to spend approximately 80% of my time pursuing scientific research. Patient care and teaching responsibilities as a pulmonary and critical care attending will occupy the remainder of my time and help to keep me focused on the diseases that drive our research efforts. I plan to use the K08 award to build upon my initial work on lentiviral manipulation of alveolar macrophages and the role that these cells play in emphysema pathogenesis. During this time, I plan to develop my research career by: 1) laying an educational foundation in immunology through a combination of formal coursework and regular attendance at a weekly pulmonary immunology conference to discuss my research and that of others; 2) expanding my technical repertoire to include additional skills central to a career in molecular biology research; 3) using the assets acquired in numbers 1 and 2 above to extend and broaden my work to date; and 4) transitioning from a mentored research environment to one of independent scientific inquiry. Patients with alpha-1 antitrypsin (AAT) deficiency have decreases in circulating blood and lung epithelial lining fluid AAT that ultimately lead to panacinar emphysema, particularly in the setting of cigarette smoke exposure. Current therapy for patients with impaired lung function resulting from AAT deficiency is replacement via weekly infusions of AAT from pooled human plasma.4 This treatment is expensive, inefficient (only a small fraction of the infused AAT reaches the lung),5 and involves a lifetime of exposure to human blood products and the risks that accompany such exposure. A comprehensive understanding of AAT biology is lacking and has been a major barrier to development of new treatments for AAT deficient patients. Although it has long been known that AAT functions to inactivate neutrophil elastase in the lung, it has only recently been recognized to have a variety of alternative and significant biological effects. In particular, the effects that AAT exerts on signaling of the key transcription factor nuclear factor-kB (NF-kB) are not well understood. The goals of this proposal are first, to better understand the relationship between AAT and NF-kB to help further our knowledge of emphysema pathogenesis; and second, to test a potential gene therapy for AAT deficiency based on local expression of the normal human AAT protein in the alveolar macrophage (AM), the cell type most implicated in lung destruction in AAT deficient patients. To accomplish these goals, the investigators have developed a new tool allowing tracking of NF-kB activity in live animals, something that was not previously possible. The experiments outlined further develop this tool and then use it to help test whether anti-inflammatory effects exerted by AAT in the lung are accompanied by suppression of NF-:B translocation and additionally whether AAT deficiency is characterized by chronic activation of NF-:B signaling. They test the effects of manipulating NF-:B signaling in the setting of cigarette smoke exposure. They then proceed to test whether or not life-long overexpression of AAT in resident AMs ameliorates emphysema via anti-inflammatory effects characterized by suppression of macrophages NF-:B activation in normal or AAT deficient mice. PUBLIC HEALTH RELEVANCE: Alpha-1 antitrypsin (AAT) deficiency is one of the most common hereditary lung diseases world-wide. Findings helping to explain how AAT protects the lung in the setting of injury are therefore likely to have great significance. Any novel treatment capable of affecting progression of emphysema will similarly have a significant long-term clinical impact.

描述(由申请人提供)：作为一名内科科学家，我的首要职业目标是利用我在研究环境中可用的工具，致力于治疗我在临床领域遇到的肺部疾病。我计划成为肺部医学学术部门的一名独立首席研究员，并将大约80%的时间用于科学研究。作为一名肺部和重症监护主治医生，病人护理和教学职责将占据我剩余的时间，有助于我专注于推动我们研究工作的疾病。我计划利用K08奖，在我最初关于慢病毒操纵肺泡巨噬细胞以及这些细胞在肺气肿发病机制中所起作用的工作的基础上再接再厉。在此期间，我计划通过以下方式发展我的研究生涯：1)通过正规课程和定期出席每周一次的肺部免疫学会议，奠定免疫学的教育基础，讨论我和其他人的研究；2)扩大我的技术储备，包括对分子生物学研究生涯至关重要的其他技能；3)利用上述数字1和2中获得的资产，扩展和拓宽我迄今的工作；以及4)从有指导的研究环境过渡到独立的科学探究环境。α-1抗胰蛋白酶(AAT)缺乏的患者循环血液和肺上皮细胞衬里液体AAT减少，最终导致泛腺性肺气肿，特别是在吸烟暴露的环境中。目前对AAT缺乏导致肺功能受损的患者的治疗是通过每周输注混合人血浆中的AAT来替代。4这种治疗昂贵、低效(输注的AAT只有一小部分进入肺部)，5并且涉及终生接触人类血液产品和伴随这种接触的风险。缺乏对AAT生物学的全面了解，一直是开发AAT缺乏患者新治疗方法的主要障碍。虽然人们很早就知道AAT具有灭活肺中中性粒细胞弹性蛋白酶的功能，但直到最近才发现它具有多种替代的和显著的生物学效应。特别是，AAT在关键转录因子核因子-kB(NF-kB)信号转导中的作用尚不清楚。这项建议的目标是：第一，更好地了解AAT和核因子-kB之间的关系，以帮助我们进一步了解肺气肿的发病机制；第二，基于肺泡巨噬细胞(AM)中正常人类AAT蛋白的局部表达，测试一种潜在的针对AAT缺乏症的基因治疗。肺泡巨噬细胞是与AAT缺乏患者的肺破坏最相关的一种细胞类型。为了实现这些目标，研究人员开发了一种新的工具，可以跟踪活体动物中的核因子-kB活动，这在以前是不可能的。这些实验进一步开发了这一工具，然后利用它来帮助测试AAT在肺中发挥的抗炎作用是否伴随着抑制NF-：B转位，以及AAT缺乏是否以长期激活的NF-：B信号为特征。他们测试了在香烟烟雾暴露环境中操纵核因子-：B信号的效果。然后，他们继续测试AAT在常驻AM中的终身过表达是否通过抑制正常或AAT缺陷小鼠的巨噬细胞NF-：B激活的抗炎作用来改善肺气肿。 公共卫生相关性：α-1抗胰蛋白酶(AAT)缺乏是世界范围内最常见的遗传性肺部疾病之一。因此，有助于解释AAT如何在损伤环境中保护肺的发现可能具有重要意义。任何能够影响肺气肿进展的新疗法都将同样具有重大的长期临床影响。