Mechanisms of Telomere-Induced Emphysema

端粒诱发肺气肿的机制

基本信息

批准号：
8894574
负责人：
Mary Y Armanios
金额：
$ 58.42万
依托单位：
JOHNS HOPKINS 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：
2014-07-15 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8894574
关键词：
Adult Affect Age Aging Alveolar Apoptosis Biology Cause of Death Cell Aging Cell Cycle Arrest Cell division Cell physiology Cells Characteristics Chromosomes Chronic Cigarette smoke-induced emphysema DNA DNA Damage Data Defect Development Disease Enzymes Epithelial Epithelial Cells Failure Family Figs - dietary Frequencies Functional disorder Genes Goals Habits Health Human In Vitro Inherited Injury Knockout Mice Length Link Lung Mediating Minority Modeling Mus Mutation Pathogenesis Phenotype Predisposition Premature aging syndrome Property Publishing Pulmonary Emphysema Reporting Risk Risk Factors Role Sampling Severities Signal Transduction Smoke Smoker Smoking Stem cells Telomerase Testing United States Work age related alpha 1-Antitrypsin Deficiency alveolar destruction cigarette smoking disability effective therapy environmental tobacco smoke exposure human tissue in vivo mortality mutant mutation carrier normal aging novel premature protein structure repaired response self-renewal senescence targeted sequencing telomere tool

项目摘要

DESCRIPTION (provided by applicant): Emphysema is a leading cause of disability and mortality in the United States and worldwide. Aside from cigarette smoke, age is the biggest risk factor for emphysema development. Emphysema has been considered by some as an age-related disease because the alveolar destruction that is its hallmark occurs in the normal aging lung. Telomere dysfunction is one of the best-characterized mechanisms of cellular aging. Our group has recently shown that telomere dysfunction is a determinant of emphysema susceptibility in mice as well as in some human families. This application builds on these findings to probe the mechanisms underlying telomere-mediated emphysema. Our focus is primarily on understanding how epithelial damage and cellular senescence contribute to emphysema, with age and in response to cigarette smoke. The specific aims build on compelling data showing that telomere dysfunction in epithelial cells limits repair after injury, ad test whether telomere length is a relevant determinant of stem cell function in alveolar progenitor cells. Our proposed studies aim to advance paradigms of emphysema biology in the context of aging mechanisms with the goal of identifying new understanding of disease mechanisms and novel targets for treatment.

描述（由申请人提供）：肺气肿是美国和全世界残疾和死亡的主要原因。除了吸烟之外，年龄是肺气肿发生的最大危险因素。肺气肿被一些人认为是一种与年龄相关的疾病，因为其标志性的肺泡破坏发生在正常老化的肺部。端粒功能障碍是细胞衰老最典型的机制之一。我们的研究小组最近表明，端粒功能障碍是小鼠以及某些人类家族肺气肿易感性的决定因素。该应用以这些发现为基础，探讨端粒介导的肺气肿的潜在机制。我们的重点主要是了解上皮损伤和细胞衰老如何随着年龄的增长和对香烟烟雾的反应而导致肺气肿。具体目标建立在令人信服的数据之上，这些数据表明上皮细胞中的端粒功能障碍限制了损伤后的修复，并测试端粒长度是否是肺泡祖细胞中干细胞功能的相关决定因素。我们提出的研究旨在在衰老机制的背景下推进肺气肿生物学的范例，目的是确定对疾病机制的新理解和新的治疗靶点。