Mucociliary clearance in aging

衰老过程中的粘膜纤毛清除

• 批准号: 9478026
• 负责人: Kristina L Bailey
• 金额: $ 30.85万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9478026
• 关键词: Affect; Age; Aging; Biopsy; Breathing; Cessation of life; Chronology; Cilia; Complex; Coughing; DNA Damage; DNA Double Strand Break; DNA strand break; Data; Deglutition; Elderly; Environment; EphA2 Receptor; Epithelial; Frequencies; Goals; Heart; Human; Impairment; Individual; Infection; Inhalation; Innate Immune System; Kidney; Lead; Liver; Lung; Measures; Methods; Mucociliary Clearance; Mucous body substance; Mus; Muscle; Organ; Oropharyngeal; Pathway interactions; Phenotype; Play; Pneumonia; Process; Role; Signal Transduction; Testing; Time; age group; aged; airway epithelium; endonuclease; microbial; microorganism; mortality; mouse model; normal aging; older patient; pathogen; prevent; protein expression; protein kinase C epsilon

ABSTRACT The elderly are four times more likely to develop pneumonia than younger age groups and nearly 90% of deaths due to pneumonia occur in those 65 or older. We know that mucociliary clearance is impaired in normal aging in humans, however the mechanisms of this slowing are unknown. We have recently established a mouse model of aging that will allow us to determine the mechanisms of ciliary slowing. Our supporting data suggest that increases in protein kinase C epsilon (PKCε) activity and expression of PKCε protein play a role in the slowing of ciliary beat frequency (CBF) with age. Aging is a pleotropic, complex process that can vary greatly from individual to individual. We wanted to focus on how one hallmark of aging, DNA damage, affects CBF. In addition, DNA strand breaks also play a role. We hypothesize that normal aging leads to DNA strand breaks, and elevated PKCε signaling, resulting in dysfunctional mucociliary clearance. We will test this hypothesis through the following specific aims: 1) Establish that elevated PKCε signaling slows CBF in aging, and then restore normal CBF by inhibiting this pathway. 2) Determine how double-stranded DNA breaks, a hallmark of aging, affect CBF. 3) Demonstrate that CBF is slowed in aging humans and determine the role of both double- stranded DNA breaks and PKCε in slowing CBF.

摘要 老年人患肺炎的可能性是年轻群体的四倍，近90%的人 肺炎死亡发生在65岁或以上的人群中。我们知道正常情况下粘液纤毛清除功能受损。 然而，在人类中，这种放缓的机制尚不清楚。我们最近培育了一只老鼠 这将使我们能够确定纤毛减慢的机制。我们的支持数据表明 蛋白激酶Cε活性和蛋白激酶Cε蛋白表达的增加在脑出血中起一定作用 纤毛搏动频率(CBF)随年龄增长而减慢。衰老是一个多变的、复杂的过程，变化很大。 从个人到个人。我们想把重点放在衰老的一个标志-DNA损伤-如何影响CBF。在……里面 此外，DNA链断裂也起到了一定作用。我们假设正常衰老会导致DNA链断裂， 蛋白激酶Cε信号增强，导致粘液纤毛清除功能障碍。我们将检验这一假设 通过以下具体目的：1)建立升高的PKCε信号可以延缓衰老过程中的脑血流量，进而 通过抑制这一途径恢复正常的脑血流量。2)确定双链DNA是如何断裂的，这是 衰老，影响脑血流量。3)证明脑血流量在老年人中减慢，并确定两者的作用- 滞留的dna断裂和pkcε减慢脑血流量。