Neurovascular unit dysfunction in Down syndrome revealed by TBI

项目摘要。 唐氏综合征（DS）是智力残疾最常见的遗传原因， 染色体21（Hsa 21），也称为三体21（T21）。DS患者表现出认知缺陷 并且处于发生中枢神经系统（CNS）病症的增加的风险中，包括神经和 心理障碍和阿尔茨海默病（AD）。除了AD，它与 Has 21编码的淀粉样前体蛋白的过度表达，这些CNS疾病的潜在机制， 情况大体上仍不明朗。这种知识差距阻碍了这些疾病的治疗。人 DS对环境和社会风险因素也非常敏感，例如对严重的 感染和压力引发的回归，与外部因素可以与 T21相关的遗传因素，以揭示其他微妙的预先存在的缺陷，在个人与DS。整理的丰厚 初步研究结果表明，轻度创伤性脑损伤（mTBI）是一种敏感的应激源，揭示了T21- 相关的神经血管缺陷。mTBI是由轻微的打击或头部的突然震动导致的， 神经炎症和氧化应激损伤脑细胞。它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%的人患有长期神经功能缺损。而 通过研究DS和mTBI之间的相互作用，我们最近发现了Dp 16 DS的显著易感性 模型小鼠对mTBI诱导的神经和认知障碍的反应。年轻的Dp 16小鼠表现出更长的时间 在头部受伤后立即昏迷，并显示更严重的感觉运动和认知缺陷， 后令人惊讶的是，年龄较大的Dp 16小鼠，而不是年龄匹配的对照组， 出血，表明随着年龄的增长，脑血管脆弱。此外，CtBP 2，a 由mTBI诱导的促炎性转录辅激活因子在无损伤Dp 16的脑中升高 小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， 它们是神经血管单位（NVU）的组成部分。我们推测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， 使DS脑易于发生TBI诱导的长期损伤的风险更高。为了验证这个假设，我们将 首先确定了T21相关的细胞缺陷和/或特定的候选基因如何加剧mTBI诱导的细胞凋亡。 感觉运动和认知障碍（目标1）。然后我们将定义DS中的脑血管异常 以及在mTBI的帮助下老化大脑（目标2）。我们设想这些研究将有助于建立分子 以及DS相关CNS病症的细胞基础。创伤性脑损伤，脑血管功能， DS小鼠模型，和DS生物学的这多PI团队的协作将确保成功完成 建议的研究。

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.