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: 10668968
• 负责人: Valentina Botero
• 金额: $ 0.03万
• 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/10668968
• 关键词: Affect; Area; Automobile Driving; Behavioral Symptoms; Body mass index; Brain region; Cell physiology; Central Nervous System; Cognitive; Control Animal; Data; Development; Disease; Disease Management; Dissection; Drosophila genus; Drosophila melanogaster; Excision; Exhibits; 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 Control; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Muscle Weakness; Mutate; Mutation; NF1 gene; Nervous System; 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; Symptoms; System; Testing; Transgenic Organisms; developmental disease; experimental study; gain of function; genetic manipulation; growth hormone deficiency; 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.

项目摘要/摘要 1型神经纤维瘤病是一种常见的单基因发育障碍，每3000人中就有1人患病 全世界。1型神经纤维瘤病是一种进行性发育障碍，由基因突变引起 NF1基因，编码神经纤维蛋白(NF1)。1型神经纤维瘤病患者为 容易出现一系列并发症，包括周围神经相关神经纤维瘤， 恶性肿瘤、骨骼异常、整体生长减慢和神经认知缺陷。这些 并发症严重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。新出现的研究表明，NF1的突变可能会改变新陈代谢； 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， 脑下垂体生长激素缺乏，体重指数下降。然而，NF1通过的机制 对新陈代谢的调节尚不清楚。我最近公布的数据表明，NF1通过一种 离散的神经元回路，为研究NF1介导的神经元控制机制创造了机会 新陈代谢。在这里，我建议阐明Nf1调节神经元活动的机制，导致 代谢失调，并在突变时导致神经纤维瘤病1型疾病的病理生理学。 实验将利用已建立的1型神经纤维瘤病的果蝇模型，其高度 保守的信号通路，以及生物体的实验和遗传能力来研究这一新的 NF1、神经元回路活动和新陈代谢之间的相互作用。这项研究将确定关键的信令 NF1激活的调节神经元内代谢的通路(Aim 1)及检测NF1对神经元的影响 和回路生理学，导致代谢失调(目标2)。这将通过使用全面的 以及遗传学、神经电路分析和新的功能体内成像的强大组合。总而言之， 拟议中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，并对调节NF1的神经回路进行了详细的剖析 新陈代谢影响。重要的是，辨别NF1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，特别是由中枢神经控制的症状 系统，并提供有关NF1和新陈代谢之间联系的关键信息。