Mechanisms of Teleomere-Mediated Emphysema

端粒介导的肺气肿的机制

• 批准号: 8484871
• 负责人: Jonathan K. Alder
• 金额: $ 13.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-08 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484871
• 关键词: Accounting; Acute; Age; Animal Model; Apoptosis; Binding; Biological Models; Biology; Bone Marrow; Breeding; Cell Aging; Cell Cycle Arrest; Cell Death; Cell division; Cells; Cessation of life; Characteristics; Chromosomes; Cigarette smoke-induced emphysema; Complex; Cyclin-Dependent Kinase Inhibitor; DNA Damage; DNA Sequence; DNA Structure; Data; Defect; Development; Disease; Elderly; Environment; Enzymes; Epithelial Cells; Failure; Functional disorder; Gene Expression Profile; Generations; Genetic; Goals; Health; Human; In Vitro; Individual; Injury; Investigation; Knockout Mice; Length; Link; Lung; Lung diseases; Mediating; Mediator of activation protein; Mentors; Modeling; Mus; Mutation; Pathogenesis; Pathway interactions; Peptide Hydrolases; Phase; Phenotype; Population; Predisposition; Proteins; Pulmonary Emphysema; Relative (related person); Research; Risk Factors; Role; Smoking; Stem cells; Tandem Repeat Sequences; Telomerase; Telomerase RNA Component; Telomere Shortening; Telomere-Binding Proteins; Testing; Time; Tissues; Training; United States; Work; age related; base; cell type; cigarette smoke-induced; cigarette smoking; cytokine; ds-DNA; hTR RNA; in vivo; interest; novel strategies; novel therapeutics; prevent; protein structure; repaired; response; senescence; telomere

DESCRIPTION (provided by applicant): Emphysema causes an enormous health burden within the United States and worldwide. Smoking and advanced age are the biggest risk factors for its development, yet the genetic factors that contribute to emphysema susceptibility and its associated age-related onset are largely unknown. Telomeres are DNA and protein structures that protect the ends of chromosomes. Each time a cell divides, telomeres shorten and short telomeres activate a DNA damage response that triggers cell death or cell cycle arrest. Telomere lengths are heterogeneous in the population and shorten with age; but the link between telomeres and emphysema has not been explored in animal models. This proposal builds on exciting preliminary data we have generated that mice with short telomeres are more susceptible to cigarette smoke (CS) and develop emphysema. We have found that short telomeres limit the ability of lung epithelial cells to repair and recover after injury. This projet will use mice with dysfunctional telomeres as a model system for studying emphysema biology and explore mechanisms that underlie its pathogenesis. In the first aim, we will genetically remove a key downstream regulator of cell cycle arrest following DNA damage and test if this rescues telomere-induced CS susceptibility. In the second aim, we will generate a new model to probe the consequences of telomere dysfunction in individual cell types within the lung to define the cellular basis for the emphysema susceptibility. Finally, in the third aim, we will examine the secreted proteins that mediate telomere-induced lung restructuring; this is the subject of the independent portion of this research. The proposed studies have potential to identify key pathways that contribute to emphysema pathogenesis. When identified, these mediators could potentially be targeted to treat or prevent emphysema. I have chosen an outstanding environment and group of mentors to complete the final years of my training. During the training period, I anticipate that the environment and additional training plan I have formulated will prepare me to establish an independent group that can make significant advances in translational lung research.

描述（由申请人提供）：肺气肿在美国和全世界造成巨大的健康负担。吸烟和高龄是肺气肿发生的最大危险因素，但导致肺气肿易感性及其与年龄相关的发病的遗传因素在很大程度上尚不清楚。端粒是保护染色体末端的 DNA 和蛋白质结构。每次细胞分裂时，端粒都会缩短，短端粒会激活 DNA 损伤反应，从而引发细胞死亡或细胞周期停滞。端粒长度在人群中存在异质性，并随着年龄的增长而缩短；但端粒和肺气肿之间的联系尚未在动物模型中得到探索。该提议建立在我们生成的令人兴奋的初步数据之上，即端粒短的小鼠更容易受到香烟烟雾 (CS) 的影响并患上肺气肿。我们发现短端粒限制了肺上皮细胞损伤后修复和恢复的能力。该项目将使用端粒功能失调的小鼠作为模型系统来研究肺气肿生物学并探索其发病机制。第一个目标是，我们将从基因上去除 DNA 损伤后细胞周期停滞的关键下游调节因子，并测试这是否可以挽救端粒诱导的 CS 易感性。在第二个目标中，我们将生成一个新模型来探讨肺内单个细胞类型端粒功能障碍的后果，以确定肺气肿易感性的细胞基础。最后，在第三个目标中，我们将研究 分泌的蛋白质介导端粒诱导的肺重建；这是本研究的独立部分的主题。拟议的研究有可能确定导致肺气肿发病机制的关键途径。一旦确定，这些介质可能会被用来治疗或预防肺气肿。我选择了一个优秀的环境和一群导师来完成我最后几年的训练。在培训期间，我预计我制定的环境和额外培训计划将为我建立一个能够在转化肺研究方面取得重大进展的独立小组做好准备。

项目成果

Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene.

• DOI: 10.1002/humu.22397
• 发表时间: 2013-11
• 期刊: HUMAN MUTATION
• 影响因子: 3.9
• 作者: Alder, Jonathan K.;Parry, Erin M.;Yegnasubramanian, Srinivasan;Wagner, Christa L.;Lieblich, Lawrence M.;Auerbach, Robert;Auerbach, Arleen D.;Wheelan, Sarah J.;Armanios, Mary
• 通讯作者: Armanios, Mary