Role of Mnbk in Downs Syndrome brain development & aging

Mnbk 在唐氏综合症大脑发育中的作用

• 批准号: 6723287
• 负责人: JERZY WEGIEL
• 金额: $ 51.35万
• 依托单位: INSTITUTE FOR BASIC RES IN DEV DISABIL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6723287
• 关键词: Alzheimer' s disease; Downs syndrome; Parkinson' s disease; aging; amygdala; caudate nucleus; developmental neurobiology; entorhinal cortex; hippocampus; human tissue; lenticular nucleus; memory; morphometry; motor cortex; neural degeneration; neurogenetics; neuropathology; neurophysiology; nucleus accumbens; postmortem; putamen; sensorimotor system; substantia nigra; tegmentum

DESCRIPTION (provided by applicant): We propose to integrate molecular biology, morphometry, and clinical studies to identify mechanisms leading to abnormal brain development, accelerated aging, and early onset of Alzheimer disease in people with Down syndrome (DS). We plan to conduct biochemical and morphometric studies of the memory system (hippocampus, amygdala, and entorhinal cortex) and sensory-motor system ( substantia nigra, pedunculopontine tegmental nucleus, caudal intralaminar thalamus, caudate nucleus, putamen, globus pallidus, nucleus accumbens, motor cortex, and cerebellum) in 44 people with DS. Because all people with DS develop early onset AD and some develop parkinsonian-type neurodegeneration, the mechanisms of neuronal loss in DS will be compared with temporal and topographic patterns of neuronal degeneration and loss in sporadic AD (30 cases), idiopathic PD (30 cases), and normal aging (44 cases). Our goal will be to determine: (1) the role of abnormal expression of Mnbk/DyrklA in developmental neuronal deficits in the memory and motor system of people with DS; (2) the mechanisms of synaptic abnormalities caused by excess of Mnbk/Dyrk1A protein in people with DS; (3) the role of Mnbk/Dyrk1A protein in brain accelerated aging during the fourth decade of life in people with DS; (4) the contribution of different mechanisms of neurodegeneration to dementia and motor deterioration in people with DS over 40 years of age; (5) modifications in the contribution of neurodegenerative changes to neuronal and functional loss in people with DS in comparison to normal aging, sporadic AD, and idiopathic PD. We hypothesize that in DS the extra copy of the Mnbk/Dyrk1A gene is not only a key factor in shaping structural and functional developmental abnormalities, but also affects the function of synapses in adulthood, contributes to accelerating aging of the brain, and changes the structural and functional background for development of AD and PD pathology. We hypothesize that we will be able to identify DS-specific modifications of the course of AD and PD pathology. This study will provide a foundation for identifying the mechanisms and morphological substrate of specific functional deficits, and should contribute to the improvement of diagnosis and treatment.

描述（由申请人提供）：我们建议整合分子生物学、形态计量学和临床研究，以确定导致唐氏综合征（DS）患者大脑发育异常、衰老加速和阿尔茨海默病早发的机制。我们计划对44例退行性椎体变性患者的记忆系统（海马、杏仁核和内嗅皮质）和感觉运动系统（黑质、桥脚被盖核、尾侧丘脑、尾状核、壳核、苍白球、伏隔核、运动皮质和小脑）进行生化和形态计量学研究。因为所有的退行性痴呆患者都会发展为早发性AD，一些人会发展为帕金森型神经退行性痴呆，因此将退行性痴呆的神经元丧失机制与散发性AD（30例）、特发性PD（30例）和正常衰老（44例）的神经元退行性痴呆的时间和地形模式进行比较。我们的目标将是确定：(1)Mnbk/DyrklA的异常表达在退行性痴呆患者记忆和运动系统的发育性神经元缺陷中的作用；(2)退行性痴呆患者Mnbk/Dyrk1A蛋白过量导致突触异常的机制；(3) Mnbk/Dyrk1A蛋白在退行性痴呆患者第40年大脑加速衰老中的作用；(4)不同神经退行性变机制对40岁以上退行性椎体滑移患者痴呆和运动功能减退的影响；(5)与正常衰老、散发性AD和特发性PD相比，DS患者神经退行性改变对神经元和功能丧失的贡献有所改变。我们推测，在DS中，Mnbk/Dyrk1A基因的额外拷贝不仅是形成结构和功能发育异常的关键因素，而且还影响成年期突触的功能，有助于加速大脑衰老，并改变AD和PD病理发展的结构和功能背景。我们假设我们将能够识别AD和PD病理过程中ds特异性的改变。该研究将为明确特异性功能缺陷的机制和形态学基础奠定基础，并有助于提高诊断和治疗水平。