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.

项目总结。