Neurovascular unit dysfunction in Down syndrome revealed by TBI

TBI揭示唐氏综合症的神经血管单元功能障碍

基本信息

批准号：
10518832
负责人：
MINGXIA HUANG
金额：
$ 260.18万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2022-09-07 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518832
关键词：
Acute Affect Age Alzheimer&apos s Disease American Amyloid beta-Protein Precursor Astrocytes Basement membrane Behavioral Biological Biology Blood Vessels Brain Brain Injuries Candidate Disease Gene Categories Cell Line Cells Cerebral hemisphere hemorrhage Chromosome 21 Cognitive Cognitive deficits Coma Complex Craniocerebral Trauma Defect Detection Development Disease Down Syndrome Endothelial Cells Ensure Event Exhibits Functional disorder Gene Dosage Genes Genetic Goals Head Human Human Chromosomes Hypersensitivity Immune Impaired cognition Impairment In Vitro Individual Infection Inflammation Injury Intellectual functioning disability Knowledge Link Mechanics Microglia Modeling Molecular Mus Myelin Nature Neuraxis Neurologic Neurologic Deficit Neurons Oligodendroglia Oxidative Stress Pathologic Persons Predisposition Public Health Research Personnel Research Project Grants Risk Risk Factors Sensorimotor functions Smooth Muscle Myocytes Stimulus Stress Symptoms Testing Transcription Coactivator Traumatic Brain Injury aging brain base brain cell cerebrovascular cognitive function disability experience high risk in vivo innovation insight interdisciplinary approach metabolomics mild traumatic brain injury mouse model myelination neuroinflammation neurovascular neurovascular unit novel therapeutic intervention overexpression parenchymal arterioles psychologic social stressor tool

项目摘要

PROJECT SUMMARY. Down syndrome (DS) is the most common genetic cause of intellectual disability and results from triplication of chromosome 21 (Hsa21), also known as trisomy 21 (T21). Individuals with DS demonstrate cognitive deficits and are at an increased risk of developing central nervous system (CNS) conditions, including neurological and psychological impairment, and Alzheimer’s disease (AD). With the exception of AD, which is linked to overexpression of the Has21-encoded amyloid precursor protein, the mechanisms underlying these CNS conditions remain largely unclear. This knowledge gap is hindering therapies for these conditions. People with DS are also exquisitely sensitive to environmental and social risk factors such as higher susceptibility to serious infection and to stress-triggered regression, consistent with the notion that external factors can be combined with T21-related genetic factors to reveal otherwise subtle pre-exiting defects in individuals with DS. Our exciting preliminary findings indicate that mild traumatic brain injury (mTBI) is a sensitizing stressor that reveals T21- associated neurovascular defects. mTBI results from a mild blow to or a sudden jolt of the head leading to neuroinflammation and oxidative stress that damage brain cells. It is a serious public health concern on its own, affecting ~3 million Americans each year with ~20% of them experiencing long-term neurological deficits. While examining the interaction between DS and mTBI, we recently uncovered a striking susceptibility of the Dp16 DS model mouse to mTBI-induced neurological and cognitive impairments. Young Dp16 mice exhibit a longer period of coma immediately after the head injury and display more severe sensorimotor and cognitive deficits even days later. Surprisingly, older Dp16 mice, but not age-matched controls, sustain severe post-injury intracerebral hemorrhage, indicating a cerebrovascular fragility that worsens with age. Moreover, expression of CtBP2, a proinflammatory transcriptional coactivator that is induced by mTBI, is elevated in the brains of injury-free Dp16 mice. These findings suggest the presence of T21-associated alterations in neuronal, glial, and vascular cells, which are the building blocks of the neurovascular unit (NVU). We postulate that T21 promotes NVU dysfunction through an interplay among developmental abnormalities, immune dysregulation, and oxidative stress, which predisposes the DS brain to a higher risk of TBI-induced long-term impairment. To test this hypothesis, we will firs establish how T21-related cellular defects and/or specific candidate genes exacerbate mTBI-induced sensorimotor and cognitive impairments (Aim 1). We will then define the cerebrovascular abnormalities in DS and aging brains with the aid of mTBI (Aim 2). We envision that these studies will help establish the molecular and cellular basis for DS-associated CNS conditions. The combined expertise in TBI, cerebrovascular function, DS mouse models, and DS biology of this collaborative multi-PI team will ensure the successful completion of the proposed studies.

项目摘要。唐氏综合症 (DS) 是智力障碍最常见的遗传原因，是由三倍基因引起的 21 号染色体 (Hsa21)，也称为 21 三体 (T21)，患有 DS 的个体表现出认知缺陷。患中枢神经系统 (CNS) 疾病的风险增加，包括神经系统和心理障碍和阿尔茨海默氏病 (AD)，但与此相关的 AD 除外。 Has21 编码的淀粉样前体蛋白的过度表达，这些中枢神经系统的机制这种知识差距阻碍了对这些疾病的治疗。 DS 对环境和社会风险因素也非常敏感，例如对严重疾病的易感性较高感染和压力引发的回归，与外部因素可以与外部因素相结合的概念一致 T21 相关遗传因素可揭示 DS 患者先前存在的细微缺陷。初步研究结果表明，轻度创伤性脑损伤 (mTBI) 是一种敏化应激源，可揭示 T21- 相关的神经血管缺陷是由头部轻微撞击或突然摇晃引起的。神经炎症和氧化应激会损害脑细胞，这本身就是一个严重的公共卫生问题。每年影响约 300 万美国人，其中约 20% 患有长期神经功能障碍。通过检查 DS 和 mTBI 之间的相互作用，我们最近发现 Dp16 DS 具有惊人的敏感性模型小鼠对 mTBI 诱导的神经和认知障碍的年轻 Dp16 小鼠表现出较长的时间。头部受伤后立即昏迷，甚至几天内表现出更严重的感觉运动和认知缺陷令人惊讶的是，年龄较大的 Dp16 小鼠（而非年龄匹配的对照组）出现了严重的脑损伤后症状。出血，表明脑血管脆弱性随着年龄的增长而恶化。 mTBI 诱导的促炎转录共激活因子在无损伤的大脑中升高 Dp16 这些发现表明神经元、神经胶质细胞和血管细胞中存在 T21 相关的改变，它们是神经血管单元 (NVU) 的组成部分，我们假设 T21 会促进 NVU 功能障碍。通过发育异常、免疫失调和氧化应激之间的相互作用，使 DS 大脑更容易遭受 TBI 引起的长期损伤。为了检验这一假设，我们将进行测试。首先确定 T21 相关细胞缺陷和/或特定候选基因如何恶化 mTBI 诱导的然后我们将定义 DS 中的脑血管异常。我们预计这些研究将有助于建立分子机制。 DS 相关中枢神经系统疾病的细胞基础和 TBI、脑血管功能、 DS 小鼠模型和 DS 生物学这个多 PI 协作团队将确保成功完成拟议的研究。