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: 10721999
• 负责人: Seth M Tomchik
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-11 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721999
• 关键词: 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; Life Expectancy; Link; MEKs; Mediating; Messenger RNA; Metabolic; Metabolic Control; Metabolism; Modeling; Molecular; Mutation; NF1 gene; Nature; Nervous System; Neurofibromatosis 1; Neurons; Neurotransmitters; Nutrient; Organism; PIK3CG gene; Pathway interactions; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phenocopy; Physiology; Plexiform Neurofibroma; Proteins; RNA Interference; Receptor Activation; Regulation; Research; Rest; Signal Pathway; Signal Transduction; Symptoms; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; cancer predisposition; cell type; clinically relevant; experimental study; feeding; gain of function; gene conservation; 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，影响 全球约每3500人中就有一人。致病基因编码一种名为 神经纤维素(NF1)，它主要通过RAS-GAP活动对RAS信号起到刹车的作用。NF1 影响多个下游信号级联，包括新陈代谢的中央调节。之前 研究表明，NF1的丢失可能会影响新陈代谢，但其机制，特别是在 系统层面尚不清楚。NF1对代谢过程的影响可能是或调节一些 疾病的症状，如行为改变和癌症易感性。 这个项目将测试NF1丢失如何影响体内代谢的潜在机制，使用 强大的果蝇神经纤维瘤病1型模型。完成后，我们将有一个明确的 图片：(1)在NF1中调节新陈代谢的基因和细胞信号级联 依赖方式，(2)NF1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来机械地调节外周能量储存 新的基因。NF1的高度保守性及其信号功能，以及 基本的神经回路功能原理，强调了结果的广泛适用性。 总体而言，该项目将有助于理解NF1在新陈代谢中的保守功能 神经功能，为研究NF1在生物体内的代谢效应奠定基础 以及新的治疗干预措施的未来发展。