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。PWS患者表现出 婴儿期喂养困难和发育不良，随后食欲不振和食欲过盛， 成年已知引起PWS的最小缺失涉及父代表达的神经元特异性基因簇， 核仁小RNA（snoRNA），Snord 116. Snord 116的分子靶点和功能尚不清楚。 Snord 116在对食欲控制至关重要的大脑区域中高度表达，但Snord 116的缺失如何影响食欲？ 食欲调节神经元的活性也是未知的。为了确定Snord 116损失如何改变喂养 因此，确定Snord 116在食欲调节中的分子和细胞功能至关重要 神经元大多数snoRNA在核糖体生物合成中发挥着非常保守的作用，并且在细胞内广泛表达 在组织中传播Snord 116是唯一优先在神经元中表达的。神经元具有独特的翻译能力 由于它们的大小和复杂性，神经元核糖体具有特殊的特性来满足这些需求 要求。目前尚不清楚Snord 116是否可能有助于核糖体生物发生的神经元特异性方面， 蛋白质翻译因此，我将研究Snord 116缺失对神经元蛋白翻译的影响， 控制食欲的大脑。此外，我将确定Snord 116损失对 食欲调节神经元以及这些神经元的功能障碍如何成为暴食症的基础。通过描绘 神经元特异性snoRNA的分子功能，我希望能更好地理解 蛋白质翻译是如何在神经元中调节的。在相关的食欲人群中进行这些研究- 调节神经元也使我们能够检查snoRNA和翻译在正确控制进食中的作用 大脑中的回路对食欲控制的分子基础的深入了解不仅可以更好地为我们提供信息， PWS的潜在疗法，以及肥胖症，这是儿童中日益普遍的健康问题。