Roles of Cdk5 in neurodevelopment and neurodegeneration

我们以前开发了一个系统级的度量，使我们能够推断实验样品的生理年龄（而不是其实足年龄），通过采用全基因组基因表达谱。我们还进行了实验，证明了先天免疫系统在果蝇Cdk5相关神经变性中的核心作用。在这项工作的过程中，我们偶然观察到苍蝇在无菌条件下的生长导致了它们寿命的适度延长。扩展这些观察结果的实验现在表明，我们对衰老和寿命之间关系的看法需要进行根本性的重新评估。简而言之，我们发现在果蝇的生命周期中发生的基因表达的70%的系统性变化与衰老本身的程序没有内在联系，而是更准确地被认为是免疫系统的方面，并反映了生物体进化的一系列策略的存在，以支持微生物丰富的环境中的生命。此外，从我们的考虑中去除这些以免疫为中心的衰老协变量，揭示了可能是真正的衰老过程，正如我们所说的那样，衰老的核心组成部分。这些是嗅觉，上皮屏障功能，线粒体功能和胰岛素样信号传导。 正在进行的实验正在进一步研究衰老的核心过程及其在神经退行性变和寿命确定中的作用。在其他实验中，我们还完成了实验，证明果蝇Htt，亨廷顿氏病的致病基因的直系同源物，以及阿尔茨海默氏病触发基因的果蝇同源物Appl，是调节果蝇大脑学习和记忆中心轴突生长和分支的单一生化信号通路的拮抗元件。

We previously developed a systems-level metric that allows us to infer the physiological age of an experimental sample (as opposed to its chronological age) by employing genome-wide gene expression profiling. We also performed experiments demonstrating the central role of the innate immune system in Cdk5-associated neurodegeneration in Drosophila. In the course of that work, we serendipitously observed that growth of flies under germ-free conditions led to a modest extension of their lifespan. Experiments extending those observations now suggest that our view of the relationship between aging and lifespan requires fundamental reassessment. In brief, we find that 70% of the systematic changes in gene expression that occur over the lifespan of Drosophila are not inherently linked to the program of aging itself, but rather are more accurately considered aspects of the immune system, and reflect the existence of a sequence of strategies that the organism has evolved to support life in a microbe-rich environment. Removal of these immune-centered covariates of aging from our consideration, moreover, reveals the processes that are likely to be bona fide, core components of aging as we mean that term. These are olfaction, epithelial barrier function, mitochondrial function and insulin-like signaling. Ongoing experiments are investigating further the core processes of aging and their role in neurodegeneration, and in determination of lifespan. In other experiments, we are also completing experiments demonstrating that Drosophila Htt, ortholog of the causal gene in Huntingtons Disease, and Appl, the fly homolog of the triggering gene in Alzheimers disease, are antagonistic elements of a single biochemical signaling pathway that regulates growth and branching of axons in the learning and memory center of the Drosophila brain.