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、形态测量学和临床研究，以确定导致唐氏综合症（DS）患者大脑发育异常、加速衰老和阿尔茨海默病早期发作的机制。 我们计划对记忆系统（海马体、杏仁核和内嗅皮层）和感觉运动系统（黑质、脚桥被盖核、尾层丘脑、尾状核、壳核、苍白球、伏隔核、运动皮层和运动皮层）进行生化和形态测量研究。 44 名 DS 患者中存在小脑）。由于所有 DS 患者都会出现早发性 AD，部分患者会出现帕金森型神经变性，因此 DS 中神经元丢失的机制将与散发性 AD（30 例）、特发性 PD（30 例）和正常衰老（44 例）中神经元变性和丢失的时间和地形模式进行比较。 我们的目标是确定：（1）Mnbk/DyrklA 异常表达在 DS 患者记忆和运动系统发育神经元缺陷中的作用； (2) DS患者Mnbk/Dyrk1A蛋白过量引起突触异常的机制； (3) Mnbk/Dyrk1A蛋白在DS患者四十岁时大脑加速衰老中的作用； (4) 不同的神经变性机制对40岁以上DS患者痴呆和运动功能恶化的影响； (5) 与正常衰老、散发性 AD 和特发性 PD 相比，DS 患者的神经退行性改变对神经元和功能丧失的影响有所改变。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 病理学发展的结构和功能背景。我们假设我们将能够识别 AD 和 PD 病理过程的 DS 特异性修饰。这项研究将为确定特定功能缺陷的机制和形态学基础提供基础，并有助于改进诊断和治疗。