Linking metabolism, neural function, and aging

描述（由申请人提供）：新陈代谢、衰老和神经功能之间存在根本联系。考虑到神经系统集中协调生物体代谢及其后果，理解神经系统评估生物体能量状态的精确机制对于理解衰老和年龄发病疾病至关重要。 通过色氨酸降解途径（也称为犬尿氨酸途径）的流量变化与多种神经退行性疾病（例如亨廷顿氏病、阿尔茨海默氏病、多发性硬化症和肌萎缩侧索硬化症）以及精神障碍（例如精神分裂症和抑郁症）相关。阻断色氨酸降解途径的各个点可以改善小鼠、果蝇和C.神经变性或蛋白质聚集的模型。一种氨基酸降解途径如何影响如此广泛的神经过程仍然是一个谜。在研究C.通过研究线虫摄食调节途径，我们意外地发现了一种特定的犬尿氨酸途径代谢物犬尿烯酸在动物的神经系统内局部产生，并用作食物可用性的内源性测量。我们的初步遗传和生化研究通过一个代谢产物的信号通路连接到5-羟色胺的释放，这反过来又调节神经内分泌分泌，包括胰岛素。这是通过腺苷酸能抑制特定神经元中的AMP激活激酶来实现的。由于色氨酸是一种必需氨基酸，并且各种色氨酸衍生的代谢物具有神经信号传导特性，因此我假设犬尿氨酸途径代谢物是一种古老的机制，其将代谢与神经功能联系起来，包括协调代谢、蛋白质稳态和衰老的交织途径的神经内分泌。 我建议使用C。elegans来描绘将犬尿烯酸水平与衰老和蛋白质稳态的神经内分泌机制联系起来的分子回路。我们将首先建立犬尿氨酸和特定神经元胰岛素分泌之间的精确分子联系，研究这种神经通路对生物体范围内蛋白质稳态机制的影响，并确定犬尿氨酸通路和各种长寿突变体之间的调节关系。总之，这些研究将成为神经系统如何感知新陈代谢以调节年龄相关过程的范例。

DESCRIPTION (provided by applicant): There is a fundamental connection between metabolism, aging, and neural functions. Considering that the nervous system centrally coordinates organismal metabolism and therefore its sequale, understanding the precise mechanisms through which the nervous system assesses organismal energetic state is fundamental to understanding aging and age on-set diseases. Changes in flux through the tryptophan degradation pathway, also known as the kynurenine pathway, have been linked to a variety of neurodegenerative diseases such as Huntington's, Alzheimer's, multiple sclerosis and amyotrophic lateral sclerosis as well as psychiatric disorders such as schizophrenia and depression. Blocking the tryptophan degradation pathway at various points ameliorates murine, Drosophila, and C. elegans models of neurodegeneration or protein aggregation. How one amino acid degradation pathway affects such a broad range of neurological processes remains a mystery. In the course of studying C. elegans feeding regulatory pathways, we made the unexpected discovery that a specific kynurenine pathway metabolite, kynurenic acid, is locally produced within the animal's nervous system and serves as an endogenous measure of food availability. Our preliminary genetic and biochemical studies connect this metabolite through a glutamatergic signaling pathway to serotonin release, which in turn, modulates neuroendocrine secretions including that of insulin. This is accomplished through serotonergic inhibition of AMP-activated kinase in specific neurons. As tryptophan is an essential amino acid and various tryptophan- derived metabolites have neural signaling properties, I hypothesize that the kynurenine pathway metabolites are an ancient mechanism that links metabolism to neural functions including neuroendocrine secretions that coordinate the intertwined pathways of metabolism, protein homeostasis, and aging. I propose to use C. elegans to delineate the molecular circuits that link kynurenic acid levels to neuroendocrine mechanisms of aging and protein homeostasis. We will first establish the precise molecular links between kynurenic acid and insulin secretion from specific neurons, investigate the consequences of this neural pathway on organism-wide mechanisms of proteostasis, and define the regulatory relationships between the kynurenine pathway and various longevity mutants. Together, these studies will be a paradigm for how metabolism is sensed by the nervous system to regulate age related processes.