权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Somatic mtDNA mutations in brain Aging: a single-cell approach

大脑衰老中的体细胞 mtDNA 突变：单细胞方法

基本信息

批准号：
7483970
负责人：
Konstantin Khrapko
金额：
$ 9.76万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7483970
关键词：
Affect Age Aging Area Brain Brain Part Cells Cerebellum Cerebral cortex Clonal Expansion Collaborations Collection Consensus Cytogenetics DNA DNA Sequence Data Defect Deterioration Development Disease Employee Strikes End Point Fluorescent in Situ Hybridization Framingham Heart Study Funding Genetic Genomics Goals Health Heart Hippocampus (Brain)Human Individual Inherited Institutes Interdisciplinary Study Longevity Measurement Medicine Memory Loss Mental Depression Methodology Methods Mitochondria Mitochondrial DNA Mitochondrial Diseases Monitor Movement Mus Mutation Mutation Detection Nature Nerve Degeneration Neurons Numbers Oxidative Stress Parkinson Disease Parkinsonian Disorders Patients Phenotype Pigments Point Mutation Polymerase Chain Reaction Population Power Plants Premature aging syndrome Prevalence Procedures Process Purkinje Cells Rate Research Research Personnel Respiratory Chain Role Sampling Specialist Structure of choroid plexus Substantia nigra structure Symptoms Techniques Technology Testing Tissues Variant Work age related aged aging brain cell type color detection cost interest medical schools mitochondrial DNA mutation motor impairment mutant new technology novel programs putamen respiratory single molecule success

项目摘要

The long-term goal of the proposed research is to study the mechanisms responsible for age-related dege- nerative processes. The understanding of these mechanisms may help to find ways to slow down the corres- ponding processes thus moving the onset of deterioration outside the normal human lifespan. Accumulation of mtDNA mutations has been long hypothesized as a probable cause of the various symptoms of aging, however, proof of such involvement was lacking. There is no consensus regarding which tissues and/or cell types if any are most likely to be affected. Our recent research has demonstrated unprecedented accumulation of mtDNA deletions in the substantia nigra of the aged human brain, which results in respiratory chain defects in pigmented neurons. This demonstration is important conceptually as an example the most significant involvement of somatic mtDNA mutations in an age-related degenerative process, but it also raises questions regarding the health concequences of this process, and whether it is limited to s. nigra. The specific aims therefore are: (1) To test the hypothesis that clonal expansions of mtDNA mutations, either deletions or point mutations, cause functional defects in specific cell types of the brain, and/or cause degeneration or predispose cells to degeneration. (2) To test the hypothesis that accumulation of mtDNA deletions in pigmented neurons of substantia nigra contributes to the development of Mild Parkinsonian Signs in seniors. We will compare the prevalence of cells with mtDNA deletions in a collection of well- characterized brains with respect to the presence of parkinsonian signs. (3) To develop new methodologies for mtDNA mutation quantification in individual cells. The methods include mtDNA Fluorescent In Situ Hybridization (FISH) for quantification of mtDNA deletions, and a novel massive parallel 454 DNA sequencing approach for studying mtDNA point mutations. In short, we have discovered a novel, common, age-related degenerative process in the brain involving the DNA of mitochondria, the power plants of the cell. This process affects an area involved in Parkinson's disease. We are therefore exploring if the process is responsible for movement problems widespread among the senior population. We are also testing whether similar processes affect other parts of the aging brain.

这项拟议研究的长期目标是研究与年龄相关的疾病的发生机制。神经过程。对这些机制的理解可能有助于找到减缓岩心运动的方法- 因此，积水过程使恶化的开始超出了正常人类的寿命。积累长期以来，线粒体DNA突变一直被认为是各种衰老症状的可能原因，然而，缺乏这种参与的证据。对于哪些组织和/或细胞还没有达成共识类型(如果有的话)最有可能受到影响。我们最近的研究证明了前所未有的线粒体DNA缺失在老年人脑黑质中的积累，导致色素神经元的呼吸链缺陷。作为一个例子，这个演示在概念上很重要体细胞线粒体DNA突变在与年龄相关的退化过程中最重要的参与，但它也对这一过程的健康后果以及是否仅限于S提出了疑问。因此，具体目的是：(1)检验线粒体DNA突变的克隆性扩展，缺失或点突变，导致特定脑细胞类型的功能缺陷，和/或导致使细胞退化或使细胞易于退化。(2)检验线粒体DNA积累的假设黑质着色神经元缺失与轻度帕金森病的发生高年级学生的手势。我们将比较细胞和线粒体DNA缺失的患病率根据帕金森症状的存在而表现出大脑特征的。(三)创新方法论用于单个细胞中线粒体DNA突变的量化。方法包括线粒体DNA原位荧光检测用于mtDNA缺失定量的杂交(FISH)和一种新的大规模平行454 DNA 研究mtdna点突变的测序方法。简而言之，我们在大脑中发现了一种新的、常见的、与年龄相关的退化过程，包括线粒体的DNA，细胞的动力装置。这一过程影响了帕金森氏症涉及的一个区域疾病。因此，我们正在探索这一过程是否导致了在老年人口。我们还在测试类似的过程是否会影响老化的大脑的其他部分。