Testing a novel hypothesis for a bioenergetic-endocrinological regulation of telomere dynamics

测试端粒动力学生物能量内分泌调节的新假设

基本信息

项目摘要

It is becoming evident that being healthy and functional at old age largely depends on the conditions experienced during developmental phases. Accumulating evidence suggests that the footprint of impaired early development is embedded in the length of telomeres (TL) - complexes of DNA and proteins that form protective cups at the end of chromosome - which become shorter with progressing age and exposure to oxidative stress. Many mechanisms underlying patterns of TL attrition, as well as the causal consequences for organisms are still unresolved. One major phenomenon is the shortening effect that glucocorticoids (GCs) exert on TLs at different ontogenetic stages in both humans and animals. Thus far, the actions of GCs on TL have been viewed as negative side effects since these promote oxidative stress and down-regulate telomerase activity (an enzyme for maintaining TL length). However, GCs are vital hormones without which organisms would perish within hours. The logical question therefore is: why should GCs directly cause TL shortening? I am proposing the novel hypothesis that these hormones contribute to regulating TL length during times of increased energy need by saving resources needed for TL maintenance. For example, GCs inhibit the enzyme TORC1 (Target of Rapamycin Complex 1, a regulator of cell growth), which is involved in the control of TL length. However a bioenergetics perspective of the actions of GCs on TLs has never been addressed, even though it is in line with their fundamental role in mediating energy and life-history trade-offs. This new perspective would greatly increase our understanding of TL attrition under stressful conditions, and likely enable us to find ways to counteract the adverse consequences of shortened TL. The aim of the proposed study is to investigate whether TL dynamics are one mechanism by which energetic trade-offs are resolved in, at least sometimes, an adaptive way. In the proposed study I will manipulate the energetic state of great tit (Parus major) nestlings living in the wild. I will use an avian model because avian erythrocytes have functional mitochondria, which will allow me to repeatedly measure TL dynamics in blood. I will focus on an ontogenetic stage (growth) during which TL attrition is extensive, fast and can have long lasting repercussions to test whether:1. TL shortening is induced by high energy demands (growth and variation in food availability) by comparing TL length of nestlings supplemented with nucleotides with that of controls. The same question will be evaluated from a hormonal perspective by administering GC hormones, to test this pathway for TL regulation. 2. Within a certain range, TL shortening is adaptive by quantifying physiological condition (mitochondrial activity, AMP-activated protein kinase and oxidative stress), morphological traits (mass, body size) and behavioral responses (personality traits) in experimental and control nestlings.
越来越明显的是,老年人的健康和功能在很大程度上取决于发育阶段所经历的条件。越来越多的证据表明,早期发育受损的足迹嵌入在端粒(TL)的长度中-DNA和蛋白质的复合物在染色体末端形成保护杯-随着年龄的增长和暴露于氧化应激而变短。许多机制的TL磨损模式,以及生物体的因果关系的后果仍然没有得到解决。一个主要的现象是糖皮质激素(GC)在人类和动物的不同个体发育阶段对TL施加的缩短效应。 到目前为止,GC对TL的作用被视为负面副作用,因为这些促进氧化应激并下调端粒酶活性(一种用于维持TL长度的酶)。然而,GC是至关重要的激素,没有它,生物体会在几小时内死亡。因此,合乎逻辑的问题是:为什么GC会直接导致TL缩短?我提出了一个新的假设,即这些激素有助于调节TL长度在增加的能量需求的时候,通过节省TL维护所需的资源。例如,GC抑制酶TORC 1(雷帕霉素复合物1的靶标,细胞生长的调节剂),其参与TL长度的控制。然而,从生物能量学的角度来看,GC对TL的作用从未得到过解决,即使它符合它们在介导能量和生活史权衡中的基本作用。这一新的视角将大大增加我们对压力条件下目标语损耗的理解,并可能使我们能够找到抵消目标语缩短的不良后果的方法。 建议的研究的目的是调查是否TL动态是一种机制,其中精力充沛的权衡解决,至少有时,一个自适应的方式。在拟议的研究中,我将操纵生活在野外的大山雀(山雀)雏鸟的能量状态。我将使用禽类模型,因为禽类红细胞具有功能性线粒体,这将允许我重复测量血液中的TL动态。我将集中在一个个体发育阶段(生长),在此期间TL消耗是广泛的,快速的,可以有长期持久的影响,以测试是否:1。 通过比较补充核苷酸的雏鸟与对照的TL长度,高能量需求(生长和食物可用性的变化)诱导TL缩短。同样的问题将通过给予GC激素从激素的角度进行评估,以测试TL调节的这一途径。2. 在一定范围内,TL缩短是适应性的量化生理条件(线粒体活性,AMP激活的蛋白激酶和氧化应激),形态特征(质量,身体大小)和行为反应(个性特征)在实验和对照雏鸟。

项目成果

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Dr. Stefania Casagrande, Ph.D.其他文献

Dr. Stefania Casagrande, Ph.D.的其他文献

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