Genetic and molecular mechanisms of Nf1-dependent neuronal regulation of metabolism

Nf1 依赖性神经元代谢调节的遗传和分子机制

• 批准号: 10621967
• 负责人: Seth M Tomchik
• 金额: $ 43.51万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621967
• 关键词: Address; Adult; Affect; Animal Model; Automobile Driving; Behavioral; Cell physiology; Cellular Metabolic Process; Childhood; Chronic; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diabetes Mellitus; Diet; Disease; Drosophila genus; Energy Metabolism; FRAP1 gene; Foundations; Functional disorder; Future; G-Protein-Coupled Receptors; Genes; Genetic; Genetic Diseases; Genomics; Growth; Impaired cognition; Individual; Intake; Knowledge; Lead; Life Expectancy; Link; MEKs; Mediating; Messenger RNA; Metabolic; Metabolic Control; Metabolism; Modeling; Molecular; Mutation; NF1 gene; Nature; Nervous system structure; Neurofibromatosis 1; Neurons; Neurotransmitters; Nutrient; Organism; Pathway interactions; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phenocopy; Physiology; Plexiform Neurofibroma; Proteins; RNA Interference; Receptor Activation; Regulation; Research; Rest; Seeds; Signal Pathway; Signal Transduction; Symptoms; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; cancer predisposition; cell type; clinically relevant; experimental study; feeding; gain of function; in vivo; inhibitor; insight; knock-down; loss of function; metabolic phenotype; metabolic rate; mutant; neurochemistry; neurofibroma; neuron loss; neuronal circuitry; novel; novel strategies; novel therapeutic intervention; novel therapeutics; optogenetics; overexpression; ras GTPase-Activating Proteins; rational design; sugar; transcriptome sequencing; treatment strategy; tumor

Project Summary Neurofibromatosis type 1 is a relatively common monogenetic, multisystemic disorder that affects approximately one in 3,500 individuals worldwide. The causative gene encodes a protein called neurofibromin (Nf1), which essentially acts as a brake on Ras signaling via Ras-GAP activity. Nf1 affects multiple downstream signaling cascades, including central regulators of metabolism. Prior studies have suggested that loss of Nf1 may affect metabolism, but the mechanisms, particularly at the systemic level are unclear. Nf1 effects on metabolic processes may underlie or modulate some of the symptoms of the disease, such as behavioral alterations and cancer predisposition. This project will test the mechanisms underlying how loss of Nf1 affects metabolism in vivo, using the powerful Drosophila model for neurofibromatosis type 1. Upon completion, we will have a clear picture of: (1) the genes and cellular signaling cascades that regulate metabolism in an Nf1- dependent manner, (2) how Nf1 functions in neuronal circuits to regulate metabolism through central control, (3) the neurotransmitters and/or peptides that are involved in the central control of metabolic regulation, (4) how loss of Nf1 mechanistically regulates peripheral energy stores through the effects of novel genes. The highly conserved nature of Nf1 and its signaling functions, as well as fundamental neuronal circuit functional principles, underscores the broad applicability of the results. Overall, this project will contribute to understanding conserved Nf1 functions in metabolism and neuronal function, laying the foundation for research into metabolic effects of Nf1 across organisms and future development of novel therapeutic interventions.

项目摘要 1型神经纤维瘤病是一种相对常见的单基因多系统疾病， 全世界每3,500人中就有一个。致病基因编码一种蛋白质， 神经纤维蛋白（Nf1），其基本上通过Ras-GAP活性对Ras信号传导起制动作用。NF1 影响多个下游信号级联，包括代谢的中央调节器。之前 研究表明，Nf1的损失可能会影响代谢，但机制，特别是在 系统层面不清楚。nf1对代谢过程的影响可能是某些 疾病的症状，如行为改变和癌症易感性。 该项目将使用以下方法测试Nf 1损失如何影响体内代谢的机制： 1型神经纤维瘤病的强大果蝇模型。完成后，我们将有一个明确的 图片：（1）基因和细胞信号级联调节Nf1- 依赖性方式，（2）Nf 1如何在神经元回路中发挥作用，通过中枢调节代谢 控制，（3）参与代谢的中枢控制的神经递质和/或肽 调节，（4）Nf1的损失如何通过影响机制调节外周能量储存 新的基因。Nf1的高度保守性及其信号传导功能，以及 基本神经元电路功能原理，强调了广泛的适用性的结果。 总的来说，这个项目将有助于了解保守的Nf1功能的代谢， 神经元功能，为研究Nf1在生物体中的代谢作用奠定了基础 以及未来新型治疗干预的发展。