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症患者（DS）中阿尔茨海默氏病异常发育，加速衰老和阿尔茨海默病早期发作的机制。 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小脑）有44人患有DS。由于所有DS患者都会发展早期发作，有些人会发展出帕金森型神经退行性变性，因此DS中神经元丧失的机制将与零星AD的神经元变性和丧失的时间和地形模式进行比较（30例），特发性PD（30例PD（30例）和正常AGING（44例）。 我们的目标是确定：（1）MNBK/Dyrkla在发育神经元缺陷中的异常表达在具有DS的人的记忆和运动系统中的作用； （2）DS患者的MNBK/DYRK1A蛋白过量过量引起的突触异常的机制； （3）在生命的第四个十年中，MNBK/DYRK1A蛋白在DS患者中的脑衰老中的作用； （4）在40岁以上的人群中，神经退行性机制对痴呆症的不同机制和运动恶化的贡献； （5）与正常衰老，零星AD和特发性PD相比，DS的神经退行性变化对神经元和功能丧失的贡献的修改。我们假设在DS中，MNBK/DYRK1A基因的额外副本不仅是塑造结构和功能发育异常的关键因素，而且还影响了成年后突触的功能，也有助于加速大脑的衰老，并改变AD和PD PD PD PD PD PD PD且PD PD途径的结构和功能。我们假设我们将能够识别AD和PD病理过程的DS特定修饰。这项研究将为识别特定功能缺陷的机制和形态底物提供基础，并应有助于改善诊断和治疗。