Mucociliary clearance in aging

摘要 老年人患肺炎的可能性是年轻人的四倍， 肺炎导致的死亡发生在65岁或65岁以上的人群中。我们知道正常情况下， 然而，这种减缓的机制尚不清楚。我们最近建立了一种小鼠 老化的模型，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C ε（PKCε）活性的增加和PKCε蛋白表达的增加在心肌细胞凋亡中起作用。 睫状体搏动频率（CBF）随年龄增长而减慢。衰老是一个多变的、复杂的过程， 从个人到个人。我们想关注衰老的一个标志，DNA损伤，如何影响CBF。在 此外，DNA链断裂也起作用。我们假设正常的衰老会导致DNA链断裂， 和升高的PKCε信号传导，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信号转导在衰老中减缓CBF，然后 通过抑制这一通路恢复正常的CBF。2)确定双链DNA是如何断裂的， 衰老影响脑血流3)证明CBF在老年人中减慢，并确定两个双- 链DNA断裂和PKCε在减慢CBF中的作用。

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.