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Neurovascular functions of a small RNA Snord118-mediated ribosome biogenesis

小RNA Snord118 介导的核糖体生物发生的神经血管功能

基本信息

批准号：
10355240
负责人：
Jianfu Chen
金额：
$ 45.38万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10355240
关键词：
Adolescence Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Animal Model Astrocytes Base Pairing Behavioral Binding Biogenesis Biology Blood Vessels Brain Cells Cerebrovascular Circulation Chemicals Code Cognitive Coupled Cyst Data Defect Dementia Detection Development Diffuse Disease Endothelial Cells Event Functional disorder Generations Genetic Gliosis Goals Hemorrhage Human Impaired cognition Impairment Knock-in Mouse Lead Leukoencephalopathy Maps Mediating Messenger RNA Methods Microglia Microvascular Dysfunction Modeling Modification Molecular Motor Mus Mutation Myelin Names Neurodegenerative Disorders Neuroglia Neurologic Neurons Oligodendroglia Organ Outcome Paris, France Pathologic Pathology Patients Pericytes Phenotype Point Mutation Process Proteins Psoralens RNA RNA analysis RNA, Ribosomal, 28S Resolution Ribosomal Proteins Ribosomal RNA Ribosomes Small Nucleolar RNA Small RNA Smooth Muscle Myocytes Specificity Structure Structure-Activity Relationship Technology Testing Tissues Untranslated RNA Vascular Smooth Muscle White Matter Disease base blood-brain barrier permeabilization calcification cell type crosslink genome-wide improved in vivo motor disorder mouse model nervous system disorder neurovascular neurovascular unit single molecule white matter white matter change white matter injury

项目摘要

PROJECT SUMMARY / ABSTRACT Dysfunction of neurovascular unit (NVU) contributes to diffuse white matter disorder associated with small- vessel disease (SVD), which affects approximately 50% of all dementia, including Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD). Ribosomopathies are a group of human disorders caused by mutations in ribosomal proteins or ribosome biogenesis factors. How dysregulation of a universal ribosome biogenesis process leads to tissue-specific phenotypes remains poorly understood. The goal of this proposal is to develop two new genetic mouse models for SVD and use them to determine how NVU cell type(s) are selectively vulnerable to the disruption of a ubiquitous ribosome biogenesis process. We will focus on noncoding RNA Snord118, which encodes a ribosome biogenesis factor. Snord118 point mutations in humans lead to SVD named leukoencephalopathy with calcifications and cysts (LCC), which represents the first purely neurological disorder in ribosomopathies. We have assembled the following preliminary data: 1) generated two independent disease point mutation knock-in (KI) mouse models, which display patient-like motor and cognitive behavioral abnormalities; 2) identified pericyte loss, and microvascular and white matter injury in these Snord118 KI mouse brains, which reflects the vascular unit impairment without causing lethal hemorrhage; 3) developed a new crosslinking and sequencing based technology named PARIS to high throughput map RNA structures and RNA-RNA interactions at single molecule and genome-wide levels with base-pair resolution; 4) used PARIS and identified Snord118 targets in mouse brains at early developmental stage. Preliminary data led us to hypothesize that Snord118 mutation-mediated disruption of ribosome biogenesis selectively affects NVU cells via targeting rRNAs and non-rRNAs leading to LCC-like phenotypes. To test this hypothesis, two specific aims are proposed. Aim 1 will establish mouse models of LCC and identify how NVU cell(s) are selectively affected by Snord118 mutations. Aim 2 will use PARIS coupled with KI mice to identify Snord118 targets in vivo and determine Snord118 RNA structure-function relationships. Using our new KI mice and latest PARIS, this study will generate the first tractable mouse models that do not currently exist for Snord118 LCC, identify mechanisms of Snord118 action and LCC disease, uncover a previously unknown vulnerability of specific NVU cells to the disruption of a ubiquitous ribosome biogenesis process, therefore help to reconcile the neurological phenotype specificity of ribosomopathies with the global requirement of ribosome biogenesis in all cells.

项目摘要/摘要