Adaptive glycolysis as a regulator of neuronal function and decline

适应性糖酵解作为神经元功能和衰退的调节剂

• 批准号: 10722822
• 负责人: Aaron Wolfe
• 金额: $ 12.58万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722822
• 关键词: Aging; Alzheimer' s Disease; Animal Behavior; Apoptosis; Award; Behavior; Behavioral; Biology; Biosensor; Brain; Caenorhabditis elegans; Calcium; Calcium Signaling; Career Mobility; Categories; Cells; Characteristics; Chemotaxis; Chronic; Collaborations; Colon; Communication; Complement; Data; Defect; Disease Progression; Equilibrium; Exposure to; Faculty; Fructose; Functional disorder; Genetic; Glucose; Glycolysis; Goals; Homeostasis; Hypoxia; Image; Impairment; In Vitro; Individual; Ion Channel; Learning; Link; Longevity; Measures; Mediating; Mentorship; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Monitor; NADP; Neuronal Dysfunction; Neurons; Neurophysiology - biologic function; Neurosciences; Occupations; Opsin; Orthologous Gene; Oxidation-Reduction; Pathway interactions; Pentosephosphate Pathway; Phase; Production; Proteins; Research; Resolution; Rest; Sodium Chloride; Source; Specific qualifier value; Stimulus; Stress; System; Techniques; Time; Tissues; Training; Universities; Visualization; Visualization software; Work; age related; assay development; blood glucose regulation; career; career development; cost; experience; functional decline; glucose metabolism; glucose uptake; in vivo; insight; network dysfunction; neural; neuronal metabolism; novel; prevent; response; sensor; skills; tool

A foundational, unanswered question of neural metabolism is whether the dramatic reduction in glucose uptake observed during aging and Alzheimer's disease progression is a cause or consequence of the functional decline of neurons. Current methods for visualizing the dynamics and effects of metabolism in vivo are too limited to determine if this plays a role in eventual neuronal dysfunction. Notably, neurons are thought to primarily use glucose for redox protection via the pentose phosphate pathway (PPP), rather than for production of ATP by glycolysis, and when glycolysis is upregulated in neurons in vitro it leads to elevated redox damage and apoptosis. As neuronal stimulation can also temporarily increase glycolytic flux, this suggests there may be an uncharacterized competitive regulation of glucose use towards balancing either ATP production or redox protection. Therefore, the goal of this proposal is to develop and utilize genetically-encoded biosensors for key metabolites in C. elegans neurons to determine the relationship between elevated calcium activity, dynamic states of glucose metabolism, and redox balance at single cell resolution. Thus, aim 1 of this proposal will utilize the novel fluorescent sensor HYlight to dynamically measure changes in cellular glycolysis in vivo during conditions of energy stress, such as with neuronal stimulation. The main goals of this aim are to (1) determine the relationship between states of high ATP demand and induction of upregulated glycolysis, and (2) elucidate the molecular mechanisms that enhance glycolysis under these conditions. Aim 2 will determine whether states of high neuronal glycolysis also lead to increased redox sensitivity in single neurons. Genetically-encoded biosensors for ROS and NADPH will be used to read out cellular redox state and enable development of an assay for quantifying degradation in stimulation-induced calcium activity that results from cell-autonomous ROS accumulation. Finally, the effects of reducing glucose within a single neuron over the lifespan of aging worms will be compared in the context of calcium activity and behavior to determine whether these effects coincide with those induced by elevated redox damage. This system described herein would provide a new avenue for assessing the source and impact of ROS-induced decline and give significant insight into the importance of balancing glucose metabolism in maintaining neuronal function and behavior during aging. Additionally, it will provide important career development for the submitting candidate, who will train during the K99 phase under the mentorship of Dr. Daniel Colón-Ramos at Yale University. This lab has significant expertise in behavioral neuroscience, which will be critical for advancing the career goals of the candidate in linking single neuron biology to behavioral changes during aging. This award will also support the candidate’s career goals by providing an opportunity to learn critical research skills, mentorship expertise, and personalized guidance for navigating the faculty job search. With this training the candidate will be able to successfully complete the proposed research and transition to an independent faculty career.

神经代谢的一个基本的，未解决的问题是葡萄糖摄取的急剧减少