权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of Teleomere-Mediated Emphysema

端粒介导的肺气肿的机制

基本信息

批准号：
8803454
负责人：
Jonathan K. Alder
金额：
$ 24.9万
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/8803454
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 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.

项目总结/文摘