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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

基本信息

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
项目类别：
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

项目摘要

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