Neuronal Mechanisms of Neurofibromin-Mediated Modulation of Metabolic Homeostasis

神经纤维蛋白介导的代谢稳态调节的神经机制

• 批准号: 10669356
• 负责人: Valentina Botero
• 金额: $ 3.04万
• 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: 2022-07-01 至 2023-05-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669356
• 关键词: Affect; Area; Automobile Driving; Behavioral Symptoms; Body mass index; Brain region; Cell physiology; Cognitive; Control Animal; Data; Development; Disease; Disease Management; Dissection; Drosophila genus; Drosophila melanogaster; Excision; Exhibits; Experimental Genetics; Functional Imaging; Functional disorder; Future; Genetic; Genetic Models; Growth; Homeostasis; Image; Individual; Laboratory Organism; Learning Disabilities; Life Expectancy; Link; MEKs; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Muscle Weakness; Mutate; Mutation; NF1 gene; NF1 mutation; Nervous system structure; Neuraxis; Neurobehavioral Manifestations; Neurocognitive Deficit; Neurofibromatosis 1; Neurons; Operative Surgical Procedures; Outcomes Research; Pathway interactions; Patients; Peripheral Nerves; Pharmacologic Substance; Physiology; Population; Proteins; Publishing; Quality of life; Ras/Raf; Regulation; Research; Risk; Role; Seizures; Series; Signal Pathway; Signal Transduction; Somatotropin; Sum; Symptoms; System; Testing; Transgenic Organisms; developmental disease; experimental study; genetic manipulation; growth hormone deficiency; imaging genetics; in vivo; in vivo imaging; innovation; insight; insulin sensitivity; loss of function; loss of function mutation; metabolic rate; mutant; neural circuit; neurofibroma; neuronal circuitry; novel; optical imaging; pleiotropism; rational design; skeletal abnormality; targeted treatment; therapy design; tumor; vascular abnormality

PROJECT SUMMARY/ABSTRACT Neurofibromatosis type 1 is a common monogenic developmental disorder, affecting 1 in 3,000 individuals worldwide. Neurofibromatosis type 1 is a progressive developmental disorder caused by mutations in the NF1 gene, which encodes for the protein neurofibromin (Nf1). Neurofibromatosis type 1 patients are predisposed to developing a range of complications, including peripheral nerve associated neurofibromas, malignant tumors, skeletal abnormalities, reduced overall growth, and neurocognitive deficits. These complications significantly affect patients’ quality of life and contribute to the overall decreased life expectancy of those with the disease. Emerging studies suggest that mutations in NF1 may alter metabolism; neurofibromatosis type 1 patients exhibit multisystemic symptoms and abnormalities such as short stature, pituitary growth hormone deficiencies, and reduced body mass indexes. However, the mechanism by which Nf1 modulates metabolism is unknown. My recently published data suggest that Nf1 regulates metabolism via a discrete neuronal circuit, creating the opportunity to study the mechanisms of Nf1-mediated neuronal control of metabolism. Here, I propose to elucidate the mechanisms by which Nf1 regulates neuronal activity, leading to metabolic dysregulation and contributing to neurofibromatosis type 1 disease pathophysiology when mutated. Experiments will leverage the well-established Drosophila model of neurofibromatosis type 1, its highly conserved signaling pathways, and the organism’s experimental and genetic power to study the novel interactions between Nf1, neuronal circuit activity, and metabolism. This research will identify the key signaling pathway activated by Nf1 to regulate metabolism within neurons (Aim 1) and test the effects of Nf1 on neuronal and circuit physiology, leading to metabolic dysregulation (Aim 2). This will be achieved using a comprehensive and powerful combination of genetics, neural circuit analysis, and novel functional in vivo imaging. In sum, the proposed research is among the first studies to use optical imaging to study a central neuronal circuit that has been shown to regulate metabolism and provide a detailed dissection of the neural circuits mediating Nf1 metabolic effects. Importantly, discerning the effect of Nf1 on metabolic rate will be essential in understanding the multisystemic symptoms of neurofibromatosis type 1, particularly those controlled by the central nervous system, and provide critical information on the link between Nf1 and metabolism.

项目总结/摘要 1型神经纤维瘤病是一种常见的单基因发育障碍，每3,000人中就有1人患病 国际吧1型神经纤维瘤病是一种进行性发育障碍， NF 1基因，编码神经纤维蛋白（Nf 1）。神经纤维瘤病1型患者是 易发生一系列并发症，包括周围神经相关的神经纤维瘤， 恶性肿瘤、骨骼异常、总体生长降低和神经认知缺陷。这些 并发症显著影响患者的生活质量，并导致总体预期寿命下降 那些患有这种疾病的人。新的研究表明，NF 1的突变可能会改变代谢; 1型神经纤维瘤病患者表现出多系统症状和异常如身材矮小， 垂体生长激素缺乏，体重指数降低。然而，Nf 1的机制 调节新陈代谢的机制尚不清楚我最近发表的数据表明，Nf 1通过一种 离散的神经元回路，创造了机会，研究Nf 1介导的神经元控制的机制， 新陈代谢.在这里，我建议阐明Nf 1调节神经元活动的机制，导致 代谢失调，并在突变时导致1型神经纤维瘤病的病理生理学。 实验将利用成熟的1型神经纤维瘤病果蝇模型，其高度 保守的信号通路，以及生物体的实验和遗传能力，以研究新的 Nf 1、神经元回路活动和代谢之间的相互作用。这项研究将确定关键信号 Nf 1激活的神经元内代谢调节通路（目的1），并测试Nf 1对神经元内代谢的影响。 和电路生理学，导致代谢失调（目标2）。这将通过一个全面的 以及遗传学、神经回路分析和新型功能性体内成像的强大组合。总之， 拟议的研究是第一批使用光学成像来研究中枢神经回路的研究之一， 已被证明可以调节新陈代谢，并提供了介导Nf 1的神经回路的详细解剖 代谢效应重要的是，辨别Nf 1对代谢率的影响对于理解 1型神经纤维瘤病的多系统症状，特别是那些由中枢神经系统控制的症状， 系统，并提供NF 1和代谢之间的联系的关键信息。