Non-coding RNA regulation of neuronal protein translation and appetite control

非编码RNA调节神经元蛋白质翻译和食欲控制

• 批准号: 10751087
• 负责人: Courtney Michelle Whilden
• 金额: $ 4.19万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2026-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751087
• 关键词: Adult; Affect; Appetite Stimulants; Base Pairing; Binding Sites; Biogenesis; Biological Assay; Biology; Brain; Brain region; Cell Nucleus; Cell physiology; Child; Childhood; Data; Defect; Desire for food; Eating; Electrophysiology (science); Exhibits; Failure to Thrive; Fasting; Feeding behaviors; Functional disorder; Future; Genetic; Goals; Health; Hyperphagia; Hypothalamic structure; Immunohistochemistry; Immunoprecipitation; Impairment; Individual; Link; Mediating; Messenger RNA; Molecular; Molecular Target; Mus; Neurodevelopmental Disorder; Neuronal Dysfunction; Neurons; Northern Blotting; Obesity; Physiology; Play; Population; Prader-Willi Syndrome; Property; Protein Biosynthesis; Proteins; RNA Processing; Regulation; Ribosomal RNA; Ribosomes; Role; Satiation; Site; Slice; Small Nucleolar RNA; Structure of nucleus infundibularis hypothalami; Testing; Tissues; Translations; Untranslated RNA; Viral; Work; computer studies; crosslink; feeding; infancy; insight; interest; laboratory experiment; microdeletion; novel; novel therapeutics; polysome profiling; postnatal; ribosome profiling

ABSTRACT Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder with no cure. Individuals with PWS exhibit feeding difficulties and failure-to-thrive in infancy followed by an insatiable appetite and hyperphagia in adulthood. The smallest deletions known to cause PWS involve a paternally expressed cluster of neuron-specific small nucleolar RNAs (snoRNAs), Snord116. The molecular targets and functions of Snord116 are not known. Snord116 is highly expressed in brain regions critical for appetite control, but how Snord116 loss affects the activity of appetite-regulating neurons is also not known. To determine how Snord116 loss alters feeding behavior, it is critical to determine the molecular and cellular functions of Snord116 in appetite-regulating neurons. Most snoRNAs play well conserved roles in ribosome biogenesis and are ubiquitously expressed across tissues. Snord116, uniquely, is preferentially expressed in neurons. Neurons have unique translational demands due to their size and complexity, and neuronal ribosomes have specialized properties to meet those demands. It is not known if Snord116 may contribute to neuron-specific aspects of ribosome biogenesis or protein translation. Therefore, I will investigate the effect of Snord116 loss on neuronal protein translation in parts of the brain known to control appetite. Additionally, I will determine the effect of Snord116 loss on the activity of appetite-regulating neurons and how dysfunction of these neurons may underlie hyperphagia. By delineating the molecular function of a neuron-specific snoRNA, I expect to broadly contribute toward a better understanding of how protein translation is regulated in neurons. Conducting these studies in a relevant population of appetite- regulating neurons also allows us to examine the role of snoRNAs and translation in proper control of feeding circuits in the brain. The insights gained into the molecular basis of appetite control will better inform not only potential therapies for PWS but also obesity, an increasingly prevalent health problem among children.

摘要 Prader-Willi综合征(PWS)是一种无法治愈的神经发育障碍。患有PWS的个人展示 婴儿时期的喂养困难和发育不良，随后是贪得无厌的食欲和吞噬 成人期。已知的导致PWS的最小缺失涉及一组父系表达的神经元特异性 小核仁RNA(SnoRNAs)，SNORD116。SNORD116的分子靶点和功能尚不清楚。 SNORD116在大脑中对食欲控制至关重要的区域高度表达，但SNORD116的缺失如何影响 食欲调节神经元的活动也是未知的。确定SNORD116损失如何改变馈送 行为，确定SNORD116在食欲调节中的分子和细胞功能是至关重要的 神经元。大多数snoRNAs在核糖体生物发生中起着非常保守的作用，并且普遍表达 在纸巾上。SNORD116是唯一在神经元中优先表达的基因。神经元具有独特的翻译能力 由于其大小和复杂性的需求，神经元核糖体具有满足这些需求的特殊特性 要求。目前尚不清楚SNORD116是否有助于核糖体生物发生的神经元特异性方面或 蛋白质翻译。因此，我将研究SNORD116缺失对神经元蛋白质部分翻译的影响 已知的控制食欲的大脑。此外，我将确定SNORD116缺失对酶活性的影响 食欲调节神经元以及这些神经元的功能障碍是如何导致吞噬过多的。通过勾勒出 神经元特异性snoRNA的分子功能，我希望对更好地理解 蛋白质翻译是如何在神经元中被调控的。在相关的胃口人群中进行这些研究- 调节神经元也使我们能够检查snoRNAs和翻译在适当控制进食中的作用 大脑中的电路。对食欲控制的分子基础的洞察不仅将更好地告知 对于PWS的潜在治疗方法，也包括肥胖，这是一个在儿童中日益普遍的健康问题。