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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：
7223429
负责人：
JORGE A BUSCIGLIO
金额：
$ 19.25万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-03-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7223429
关键词：
Adult Affect Alzheimer&apos s Disease Amyloid Aneuploidy Apoptotic Appendix 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 Mitochondria Mitochondrial Diseases Molecular Morphology Mosaicism Muscle hypotonia Nature Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Numbers Oxidative Stress Pathogenesis Pathology Pathway interactions Patients Peripheral Play Population Predisposition Production Protein Overexpression Proteins Public Health Regulation Research Personnel Role Structure Tissue Sample Tissues Trisomy United States abeta accumulation base brain tissue congenital infection gastrointestinal improved interest leukemia middle age mitochondrial dysfunction neuropathology novel prevent programs protein metabolism research study therapy design transcription factor

项目摘要

DESCRIPTION (provided by applicant): 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 mitochondrial 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 a precursor protein (APR) metabolism and intracellular amyloid beta (Abeta) 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 neurodegenerative disorders, and to design therapies directed to prevent neuronal dysfunction and the progression of AD neuropathology in DS patients.