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Quantifying the contributions of mitochondrial DNA to Alzheimer's Disease and related conditions of aging

量化线粒体 DNA 对阿尔茨海默病和相关衰老状况的影响

基本信息

批准号：
10269143
负责人：
S. Alexandra Burt
金额：
$ 154.29万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10269143
关键词：
Aerobic Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Bacteria Biometry Birds Birth Certificates Characteristics Communities Cytoplasm DNA Data Set Death Certificates Development Diabetes Mellitus Disease Distant Elements Environment Etiology Extended Family Family Family member Fishes Food Foundations Functional disorder Future Generations Genetic Genetic Recombination Germ Cells Individual Inheritance Patterns Inherited Joints Knowledge Life Link Longevity Mammals Medical Medical Records Meiosis Methods Mitochondria Mitochondrial DNA Mitochondrial Inheritance Modeling Mothers Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Family Organelles Organism Outcome Parkinson Disease Pattern Population Population Database Probability Production Records Regulation Reproductive Process Research Role Running Sampling Sensitivity and Specificity Ships Statistical Models Suicide Symptoms Testing Time Uncertainty Update Utah Variant Walking Work asexual base genetic pedigree human disease insight interest intergenerational knowledge base mitochondrial dysfunction mitochondrial genome next generation novel offspring transmission process virtual

项目摘要

ABSTRACT Mitochondria are bacteria-like organelles with their own DNA (mtDNA). They reside in our cellular cytoplasm, and provide nearly all of the energy we use to sustain life. It thus stands to reason that inherited mtDNA dysfunction is an important element of diseases characterized by low energy. The field has yet to broadly examine this hypothesis, however, in large part because the biometric or family models we use to estimate the effects of nuclear DNA are totally incompatible with the study of mtDNA due to its unique characteristics and pattern of inheritance (e.g., mtDNA reproduces itself asexually and is transmitted directly down the maternal line). The current R01 seeks to develop, validate, and test a model that leverages this singular pattern of mtDNA inheritance to estimate the proportions of variance accounted for by variation in mtDNA (mt2). We suspect that cousins will be a particularly informative set of relatives in this regard. Matrilineal cousins, including very distant ones, share virtually all of their mtDNA. Patrilineal cousins, by contrast, do not typically share mtDNA. We will exploit this difference in the maternal and paternal lines to estimate mt2. Once developed and validated, we will run this model in a sample of ~4.8 million individuals in multigenerational pedigrees 4 to 17 generations deep, which have been linked to annually updated medical and vital records that have arisen over the last 25 years. Analyses will focus on Alzheimer's Disease (AD) and other key aging outcomes (diabetes, suicide, Parkinson's Disease, and longevity). In this way, the proposed R01 should not only yield critical new insights into the origins of AD and related conditions of aging, but will also develop novel methods to establish much needed Bayesian `priors' to guide future research in the role of mtDNA.

摘要线粒体是一种类似细菌的细胞器，有自己的DNA（mtDNA）。它们存在于我们的细胞中细胞质，并提供几乎所有的能量，我们用来维持生命。因此，有理由认为，遗传性线粒体DNA功能障碍是以低能量为特征的疾病的重要因素。的然而，该领域还没有广泛地研究这一假设，这在很大程度上是因为生物特征或我们用来估计核DNA影响的家庭模型与核DNA的研究完全不相容。 mtDNA由于其独特的特征和遗传模式（例如，线粒体DNA自我复制无性传播，并直接通过母系传播）。目前的R01寻求发展，验证和测试一个模型，该模型利用mtDNA遗传的这种单一模式来估计 mtDNA（mt2）变异占变异的比例。我们怀疑堂兄弟会是一个在这方面，亲戚们的信息量特别大。母系表亲，包括远房表亲，几乎都有相同的线粒体DNA相比之下，父系堂兄弟姐妹通常不共享mtDNA。我们将利用母系和父系的这种差异来估计MT2。一旦开发出来，经过验证，我们将在多代谱系中的约480万个体样本中运行此模型 4到17代人，这些数据与每年更新的医疗和生命记录相关联，在过去的25年里出现了。分析将集中在阿尔茨海默病（AD）和其他关键疾病上。衰老结果（糖尿病、自杀、帕金森病和长寿）。因此，建议 R01不仅应该对AD的起源和衰老的相关条件产生重要的新见解，但也将开发新的方法来建立急需的贝叶斯“先验”，以指导未来的研究mtDNA的作用。