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着根本的联系。考虑到神经系统集中协调机体代谢及其后续活动，了解神经系统评估机体能量状态的精确机制是理解衰老和年龄相关性疾病的基础。色氨酸降解途径（也称为犬尿氨酸途径）的变化与多种神经退行性疾病（如亨廷顿氏症、阿尔茨海默氏症、多发性硬化症和肌萎缩侧索硬化症）以及精神疾病（如精神分裂症和抑郁症）有关。在不同的点阻断色氨酸降解途径可以改善小鼠、果蝇和秀丽隐杆线虫的神经变性或蛋白质聚集模型。一个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。在研究秀丽隐杆线虫摄食调控途径的过程中，我们意外地发现了一种特定的犬尿氨酸途径代谢物——犬尿酸，它在动物的神经系统中局部产生，并作为一种内源性的食物可用性指标。我们的初步遗传和生化研究将这种代谢物通过谷氨酸能信号通路与血清素释放联系起来，血清素释放反过来调节包括胰岛素在内的神经内分泌分泌。这是通过血清素能抑制特定神经元中amp活化的激酶来实现的。由于色氨酸是一种必需氨基酸，各种色氨酸衍生的代谢物具有神经信号特性，我假设犬尿氨酸途径代谢物是一种古老的机制，它将代谢与神经功能联系起来，包括神经内分泌分泌，协调代谢、蛋白质稳态和衰老的相互交织的途径。我建议使用秀丽隐杆线虫来描述将尿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电路。我们将首先建立犬尿氨酸与特定神经元胰岛素分泌之间的精确分子联系，研究这一神经通路对机体蛋白质稳态机制的影响，并确定犬尿氨酸途径与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.