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

• 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
• 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' 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

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）是智力障碍的最常见遗传原因 染色体21（HSA21），也称为三体菌21（T21）。 DS的人表现出认知缺陷 并且有发展中枢神经系统（CNS）条件的风险增加，包括神经系统和 心理障碍和阿尔茨海默氏病（AD）。除了与AD相关联的AD HAS21编码的淀粉样前体蛋白的过表达，这些机制是这些CNS的基础机制 条件在很大程度上不清楚。这些知识差距阻碍了这些条件的疗法。有人 DS也对环境和社会风险因素完全敏感，例如更高的严重敏感性 感染和应力触发回归，与外部因素可以与 T21相关的遗传因素揭示了DS个体中其他细微的预测缺陷。我们令人兴奋 初步发现表明，轻度创伤性脑损伤（MTBI）是一种敏感的压力源，揭示了T21-- 相关的神经血管缺陷。 MTBI是由于轻度打击而导致的，或者突然的头部震动导致 神经炎症和氧化应激，损害脑细胞。这是一个严重的公共卫生问题， 每年影响约300万美国人，其中约有20％患有长期神经系统缺陷。尽管 检查DS与MTBI之间的相互作用，我们最近发现了DP16 DS的打击敏感性 将小鼠模拟MTBI诱导的神经系统和认知障碍。年轻的DP16小鼠暴露了更长的时间 头部受伤后立即昏迷，表现出更严重的感觉运动和认知能定义几天 之后。令人惊讶的是，较老的DP16小鼠，但不匹配年龄的对照，维持严重的伤口后脑内脑内 出血，表明脑血管脆弱性随着年龄的增长而恶化。此外，CTBP2的表达 由MTBI诱导的促炎性转录共激活因子在无损伤DP16的大脑中升高 老鼠。这些发现表明在神经元，神经胶质和血管细胞中存在T21相关的改变， 这是神经血管单元（NVU）的组成部分。我们假设T21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，这 使DS大脑容易受到TBI诱导的长期损害的较高风险。为了检验这一假设，我们将 FIR建立了与T21相关的细胞缺陷和/或特定候选基因如何加剧MTBI诱导的 感觉运动和认知障碍（AIM 1）。然后，我们将定义DS中的脑血管异常 并在MTBI的帮助下（AIM 2）衰老。我们设想这些研究将有助于建立分子 与DS相关的中枢神经系统条件的细胞基础。 TBI，脑血管功能的联合专业知识， DS鼠标模型以及该协作多PI团队的DS生物学将确保成功完成 提出的研究。