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

基本信息

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
项目类别：
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

项目摘要

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，会影响全球大约有3500个人中有一个。致病基因编码一种称为的蛋白质神经纤维蛋白（NF1）基本上通过RAS-GAP活性充当RAS信号的制动器。 NF1 影响多个下游信号级联，包括代谢的中心调节剂。事先的研究表明，NF1的丧失可能会影响新陈代谢，但是机制，特别是在系统水平尚不清楚。 NF1对代谢过程的影响可能是基础或调节的一些该疾病的症状，例如行为改变和癌症易感性。该项目将测试NF1损失如何影响体内新陈代谢的基础机制，并使用神经纤维瘤病1型的强大果蝇模型。完成后，我们将有一个清晰的图：（1）调节NF1-中代谢的基因和细胞信号传导级联依赖方式，（2）NF1在神经元电路中的功能如何通过中央调节代谢控制，（3）代谢中心控制涉及的神经递质和/或肽调节，（4）NF1的损失如何通过效应机械地调节外围能量存储新基因。 NF1及其信号函数的高度保守性质以及基本神经元电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代谢中保守的NF1功能神经元功能，为NF1跨生物的代谢作用研究奠定了基础以及新型治疗干预措施的未来发展。