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.

抽象的 老年人患肺炎的可能性是年轻群体的四倍，近 90% 65 岁或以上的老年人会因肺炎而死亡。我们知道，正常人的粘膜纤毛清除功能受到损害。 人类衰老，但这种减缓的机制尚不清楚，我们最近建立了一种小鼠。 我们的支持数据表明，衰老模型将使我们能够确定纤毛减慢的机制。 蛋白激酶 C epsilon (PKCε) 活性和 PKCε 蛋白表达的增加在 纤毛跳动频率 (CBF) 随着年龄的增长而减慢，这是一个多向性、复杂的过程，变化很大。 我们希望关注衰老的标志之一——DNA 损伤——如何影响 CBF。 此外，DNA链断裂也发挥了作用，正常衰老会导致DNA链断裂， PKCε 信号传导升高，导致粘膜纤毛清除功能障碍。我们将检验这一假设。 通过以下具体目标：1) 确定升高的 PKCε 信号传导可减缓衰老过程中的 CBF，然后 通过抑制该途径恢复正常 CBF 2) 确定双链 DNA 断裂的方式，这是双链 DNA 断裂的标志。 3) 证明 CBF 在衰老的人类中减慢，并确定两者的作用。 链状 DNA 断裂和 PKCε 会减缓 CBF。