Mitochondrial Dysfunction in Down's Syndrome

唐氏综合症的线粒体功能障碍

基本信息

批准号：
8097125
负责人：
JORGE A BUSCIGLIO
金额：
$ 5.07万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2011-06-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8097125
关键词：
Adult Affect Alzheimer&apos s Disease Amyloid Aneuploidy Apoptotic Astrocytes Birth Brain Caring Cells Childhood Chromosomes, Human, Pair 21 Chronic Chronic Disease Cultured Cells Defect Development Disease Down Syndrome Endocrine system Face Family health status Fibroblasts Funding Genetic Grant Health Personnel Heart High Prevalence Immune Impairment Incidence Individual Laboratories Lead Live Birth Medical Mental Retardation Metabolism Mitochondria Mitochondrial Diseases Molecular Morphology Mosaicism Muscle hypotonia Nature Nerve Degeneration Neuronal Dysfunction Neurons Oxidative Stress Pathogenesis Pathology Pathway interactions Patients Peripheral Play Population Predisposition Production Protein Precursors Proteins Public Health Regulation Research Personnel Role Structure Tissue Sample Tissues Trisomy United States base brain tissue congenital infection gastrointestinal improved interest leukemia middle age mitochondrial dysfunction neuropathology novel overexpression prevent programs protein metabolism research study therapy design transcription factor

项目摘要

Down's syndrome (DS) or trisomy 21 is the most common autosomal aneuploidy that survives birth and it is the single most frequent genetic cause of mental retardation. The number of DS patients in the.United States is estimated to be more than 350,000. Abnormal mitochondria! function cause selective neuronal degeneration and is associated with a variety of disorders including DS. During this grant period, we have obtained results indicating that: 1) mitochondrial dysfunction exist in DS neurons and astrocytes, which leads to aberrant amyloid (i precursor protein (APR) metabolism and intracellular amyloid IS (Afi) accumulation; 2) there are mitochondrial structural and functional alterations in DS neurons, astrocytes, fibroblast and lymphoblastoid cells; and 3) the mitochondrial localization of Mfn1 and Drp1, which are proteins that participate in the regulation of mitochondrial morphology and activity is altered in DS brains and DS cultured cells. We hypothesize that mitochondrial dysfunction in DS may lead to a persistent deficit in energy production and chronic oxidative stress, two critical factors in the development of DS neuropathology and the development of AD in DS subjects. To further understand the role of mitochondrial dysfunction in DS, we propose the following specific aims: 1) to characterize the structural and functional alterations in DS mitochondria; 2) to characterize the molecular determinants of mitochondrial dysfunction in DS; and 3) to analyze mitochondrial alterations in limphoblastoid cells of DS patients, and to determine the relevance of mitochondrial dysfunction as a predictor of AD pathology in DS. Normal and DS brain tissue samples, normal and DS cortical neurons, astrocytes and fibroblast cultures will be utilized to characterize mitochondrial structure and function and to study the molecular components involved in DS mitochondrial dysfunction. Fibroblast and limphoblastoid cells derived from normal and DS subjects will be utilized to analyze the existence of mitochondrial dysfunction in peripheral tissues, and limphoblastoid cells will be used to evaluate the relation between mitochondrial dysfunction and the presence of AD in DS subjects. These experiments will provide novel information on mitochondrial structure and function in DS that may be critical to understand the role of energy impairment in neurodegenerativedisorders, and to design therapies directed to prevent neuronal dysfunction and the progression of AD neuropathology in DS patients

唐氏综合症（DS）或三体症是21是最常见的常染色体非整倍性生存，它是最常见的智力降低遗传原因。 DS患者的数量。国家估计超过350,000。线粒体异常！功能导致选择性神经元变性，与包括DS在内的多种疾病有关。在此赠款期间，我们有获得的结果表明：1）DS神经元和星形胶质细胞中存在线粒体功能障碍，异常淀粉样蛋白（I前体蛋白（APR）代谢和细胞内淀粉样蛋白是（AFI）积累； 2） DS神经元，星形胶质细胞，成纤维细胞和淋巴母细胞； 3）MFN1和DRP1的线粒体定位，这是蛋白质参与线粒体形态的调节和活性在DS大脑和DS培养中发生了变化细胞。我们假设DS中的线粒体功能障碍可能导致能量持续不足生产和慢性氧化应激，DS神经病理发展的两个关键因素和在DS主题中开发AD。为了进一步了解线粒体功能障碍在DS中的作用，我们提出以下特定目的：1）表征DS中的结构和功能变化线粒体； 2）表征DS中线粒体功能障碍的分子决定因素；和3）到分析DS患者的林型细胞细胞中线粒体改变，并确定线粒体功能障碍是DS中AD病理学的预测指标。正常和DS脑组织样品，正常和DS皮质神经元，星形胶质细胞和成纤维细胞培养物将用于表征线粒体结构和功能，并研究与DS线粒体有关的分子成分功能障碍。衍生自正常和DS受试者的成纤维细胞和林木母细胞细胞将用于分析将使用线粒体功能障碍在外周组织中的存在，以及将使用薄细胞细胞评估线粒体功能障碍与DS受试者中AD的存在之间的关系。这些实验将提供有关DS中线粒体结构和功能的新信息，这可能是关键的了解能量障碍在神经变性词中的作用，并设计疗法指示可预防神经元功能障碍和DS患者AD神经病理学的进展

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cryopreservation of cortical tissue blocks for the generation of highly enriched neuronal cultures.

皮质组织块的冷冻保存用于生成高度富集的神经元培养物。

DOI：
10.3791/2384
发表时间：
2010
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Rahman,ArdeshirS;Parvinjah,Shaudee;Hanna,MichaelA;Helguera,PabloR;Busciglio,Jorge
通讯作者：
Busciglio,Jorge

Mitochondrial dysfunction and Down's syndrome: is there a role for coenzyme Q(10) ?