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 年龄较大的年龄段的可能性是年龄段的四倍，几乎是90％ 由于肺炎而导致的死亡发生在65岁以上。我们知道粘纤毛清除在正常情况下受到损害 但是，人类的衰老，但是这种放缓的机制尚不清楚。我们最近建立了一只鼠标 衰老模型将使我们能够确定睫状减速的机理。我们的支持数据暗示 蛋白激酶C epsilon（PKCε）的活性和PKCε蛋白的表达增加了 随着年龄的增长，睫状节拍频率（CBF）放慢。衰老是一个多元型，复杂的过程，可以变化很大 从个人到个人。我们想专注于衰老的一个标志，DNA损伤如何影响CBF。在 此外，DNA链断裂也起作用。我们假设正常衰老会导致DNA链断裂， PKCε信号传导升高，导致功能失调的粘膜纤毛清除率。我们将检验这个假设 通过以下特定目的：1）确定升高的PKCε信号在衰老中减慢了CBF，然后放慢 通过抑制此途径来恢复正常的CBF。 2）确定双链DNA如何断裂，一个标志 老化，影响CBF。 3）证明CBF在衰老的人类中有所减慢，并确定了两种双重的作用 滞留的DNA断裂和PKCε在减慢CBF中。