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 /摘要神经血管单元（NVU）功能障碍有助于弥漫性白质障碍血管疾病（SVD），影响了所有痴呆症的大约50％，包括阿尔茨海默氏病和阿尔茨海默氏病与疾病相关的痴呆症（AD/ADRD）。核糖体病是引起的一组人类疾病通过核糖蛋白或核糖体生物发生因子的突变。通用核糖体的失调如何生物发生过程导致组织特异性表型仍然很熟悉。该提议的目的是为SVD开发两个新的遗传小鼠模型，并使用它们来确定NVU细胞类型的方式有选择地容易受到普遍存在的核糖体生物发生过程的破坏。我们将重点关注非编码RNA SNORD118，它编码核糖体生物发生因子。人类中的Snord118点突变导致具有钙化和囊肿（LCC）的SVD名为Liukoencephalopathy，它代表第一个纯粹核糖体病中的神经疾病。我们已经组装了以下初步数据：1）生成两个独立的疾病点突变敲入（KI）小鼠模型，它们显示患者样电动机和认知行为异常； 2）确定周围的周细胞损失，以及其中的微血管和白质损伤 Snord118 ki小鼠大脑，反映了血管单位损伤而不会引起致命的出血。 3）开发了一种名为Paris的新的基于序列和测序的技术到高吞吐量RNA 在单分子和全基因组水平上的结构和RNA-RNA相互作用均具有碱基对分辨率； 4）在早期发育阶段使用了巴黎并确定了小鼠大脑中的SNORD118靶标。初步数据导致我们假设SNORD118突变介导的核糖体生物发生的破坏有选择地影响 NVU细胞通过靶向RRNA和非RRNA导致LCC样表型。为了检验这一假设，两个提出了具体目标。 AIM 1将建立LCC的鼠标模型，并确定NVU单元格是如何有选择地受SNORD118突变的影响。 AIM 2将使用巴黎，加上Ki小鼠来识别SNORD118 靶向体内并确定SNORD118 RNA结构 - 功能关系。使用我们的新奇鼠和最新巴黎，这项研究将生成第一个可用于SNORD118 LCC的可处理的鼠标模型，确定SNORD118动作和LCC疾病的机制，发现以前未知的脆弱性特定的NVU细胞会破坏无处不在的核糖体生物发生过程，因此有助于调和核糖体病的神经系统表型特异性符合核糖体生物发生的全球需求在所有细胞中。