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Mechanisms of Teleomere-Mediated Emphysema

端粒介导的肺气肿的机制

基本信息

批准号：
8819562
负责人：
Jonathan K. Alder
金额：
$ 24.53万
依托单位：
BRIGHAM YOUNG UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8819562
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 abstracting age related base cell type cigarette smoke-induced cigarette smoking cytokine ds-DNA environmental tobacco smoke exposure genetic approach hTR RNA in vivo interest novel strategies novel therapeutics prevent protein structure repaired response senescence telomere

项目摘要

Project Summary/Abstract 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 project 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.

项目摘要/摘要肺气肿在美国和世界范围内造成了巨大的健康负担。吸烟和高龄是该病发生的最大风险因素，而导致该病发生的遗传因素肺气肿的易感性及其与年龄相关的发病在很大程度上尚不清楚。端粒是DNA和保护染色体末端的蛋白质结构。细胞每分裂一次，端粒就会越来越短端粒激活DNA损伤反应，从而触发细胞死亡或细胞周期停滞。端粒长度为在人群中是异质性的，并随着年龄的增长而缩短；但端粒和肺气肿之间的联系没有在动物模型中被研究过。这项建议建立在我们生成的令人兴奋的初步数据的基础上端粒较短的老鼠更容易受到香烟烟雾(CS)的影响，并患上肺气肿。我们有研究发现，较短的端粒限制了肺上皮细胞在损伤后修复和恢复的能力。这个项目将利用端粒功能障碍的小鼠作为研究肺气肿生物学的模型系统，并探索其发病机制。在第一个目标中，我们将从基因上移除下游的一个密钥 DNA损伤后细胞周期停滞的调节器，并测试这是否挽救了端粒诱导的CS易感性。在第二个目标中，我们将建立一个新的模型来探索端粒功能障碍在肺内单个细胞类型以确定肺气肿易感性的细胞基础。最后，在第三个目标，我们将研究介导端粒诱导的肺重组的分泌蛋白；这是本研究的独立部分的主题。拟议的研究有可能确定关键参与肺气肿发病机制的途径。一旦确定，这些调解人可能会被以治疗或预防肺气肿为目标。我选择了一个出色的环境和一群导师来完成我最后几年的训练。在培训期间，我预计环境和我制定的额外培训计划将为我建立一个独立的小组做好准备，该小组可以使转化型肺研究的重大进展。