Neuronal Orchestration of Metabolic State and Longevity

代谢状态和寿命的神经协调

基本信息

批准号：
10372000
负责人：
Supriya Srinivasan
金额：
$ 56.19万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372000
关键词：
Adult Affect Age Aging American Automobile Driving Biochemical Biological Assay Biological Models Biology Body fat Caenorhabditis elegans Cell Culture Techniques Communication Consequentialism Data Diabetes Mellitus Elderly Environment Equilibrium Fatty acid glycerol esters Food Future Genetic Transcription Goals Health Heart Diseases Helix-Turn-Helix Motifs Homeostasis Human Intestines Knowledge Laboratories Link Lipase Longevity Metabolic Metabolic Diseases Metabolism Mitochondria Modeling Molecular Molecular Analysis Molecular Genetics Nerve Degeneration Nervous system structure Neuraxis Neurons Neurosecretory Systems Nutrient Obesity Organ Orthologous Gene Outcome Oxygen Pathway interactions Peptides Peripheral Pharmaceutical Preparations Physiological Property Regulation Role Sensory Serotonin Signal Transduction Stress System Tachykinin Tissues activating transcription factor 1 adenylate kinase alpha helix biological adaptation to stress combat common cellular transcription factor ATF design experimental study genetic approach insight lipid metabolism multimodality mutant neural circuit neuronal circuitry receptor relating to nervous system response sensor tool transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT Older adults will be disproportionately affected by the complications arising from metabolic diseases including diabetes, heart disease and neurodegeneration, predicted to double between now and 2050. However, the fundamental mechanisms that link obesity and metabolic disease with longevity remain poorly understood. The central nervous system is a major driver of lipid metabolism and lifespan. However neuroendocrine signals that specifically control metabolism and lifespan are poorly understood in any system, and cannot be modeled in cell culture. The long-term goal of my laboratory is to decipher the neural circuits and neuroendocrine mechanisms that regulate metabolism and lifespan, and to define the key regulatory principles that govern their relationship. We have uncovered an integrated neuro-metabolic system that underlies communication between the nervous system and the intestine in the C. elegans model system, in which ancient and conserved aspects of neuroendocrine biology can be discovered with state-of-the-art molecular tools. We define two critical nodes for the regulation of this neuroendocrine system: one neuronal, one metabolic. The neuronal node integrates food and oxygen sensory information from the environment, and the metabolic node integrates fat loss with mitochondrial stress. Our central hypothesis is that the neuronal and metabolic nodes counterbalance one another to maintain the integrity of neuroendocrine homeostasis, and that disruption of this counterbalancing mechanism at either node alters lifespan. The objective of this proposal is to determine the molecular mechanisms that regulate the homeostatic balance between the neuronal and metabolic nodes, and to identify the key drivers that protect longevity. Thus, our neuroendocrine pathway defines a unique and powerful model to study the consequences of neuronally-stimulated lipid metabolism, on longevity. Aim 1 will define the neural circuit mechanisms that integrate neuroendocrine signaling, fat metabolism and lifespan. Our goal is to scale multiple levels of analysis from molecular, circuit-level and organismal properties to achieve mechanistic insights how the activity of a multimodal neural circuit gives rise to coordinated physiological shifts in metabolism and longevity. Aim 2 will identify the mechanistic interactions between neuronally-driven fat loss and mitochondrial stress-sensing pathways in the intestine, which ultimately drive lifespan. Using molecular genetic approaches, biochemical analyses, metabolic and lifespan assays, we will uncover the molecular mechanisms that couple fat loss with stress-protective mechanisms that together determine longevity. A major expected outcome of our proposed studies is that longevity is an emergent property, determined by the extent to which mitochondrial stress in metabolic tissues can counterbalance the neuronal drive for fat loss. The experiments proposed in Aims 1 and 2 are expected to pinpoint, at a molecular level, the integrative mechanisms that underlie this neuroendocrine homeostasis. This knowledge is critical for the future design of safe and effective drugs to combat metabolic diseases that accompany aging.

项目摘要/摘要老年人将受到代谢性疾病（包括）的并发症的不成比例糖尿病，心脏病和神经变性，预计从现在到2050年。将肥胖和代谢疾病与寿命联系起来的基本机制仍然很少理解。这中枢神经系统是脂质代谢和寿命的主要驱动力。但是神经内分泌信号在任何系统中，特定控制的代谢和寿命都对细胞培养。我实验室的长期目标是破译神经回路和神经内分泌调节新陈代谢和寿命的机制，并定义控制其的关键监管原则关系。我们发现了一个综合的神经代谢系统，该系统是基础的秀丽隐杆线虫模型系统中的神经系统和肠道，其中古老和保守的方面可以使用最先进的分子工具发现神经内分泌生物学。我们定义两个关键节点对于这种神经内分泌系统的调节：一种神经元，一种代谢。神经元节点积分来自环境的食物和氧气信息，代谢节点将脂肪流失与线粒体应力。我们的中心假设是神经元和代谢节点的平衡一个另一个维持神经内分泌稳态的完整性，以及这种平衡的破坏任何一个节点的机制都会改变寿命。该提议的目的是确定分子调节神经元和代谢节点之间稳态平衡的机制，并确定保护寿命的主要驱动力。因此，我们的神经内分泌途径定义了一个独特而有力的模型研究神经刺激的脂质代谢对寿命的后果。 AIM 1将定义神经整合神经内分泌信号传导，脂肪代谢和寿命的电路机制。我们的目标是扩展分子，电路级和生物特性的多个分析，以实现机械见解多模式神经回路的活动如何导致协调的生理转移代谢和寿命。 AIM 2将确定神经驱动的脂肪流失之间的机械相互作用肠道中的线粒体应力感应途径最终驱动寿命。使用分子遗传方法，生化分析，代谢和寿命测定法，我们将发现分子将脂肪损失的机制与压力保护机制共同决定了寿命。专业我们提出的研究的预期结果是，长寿是一种新兴财产，取决于程度代谢组织中的线粒体应激可以抵消神经元驱动脂肪的驱动。这 AIM 1和2中提出的实验有望在分子水平上查明整合性这种神经内分泌稳态的机制。这些知识对于未来设计至关重要安全有效的药物来抵抗伴随衰老的代谢疾病。