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.

抽象的线粒体是具有自己的DNA（mtDNA）的细菌样细胞器。它们居住在我们的蜂窝细胞质，并提供几乎所有用于维持生命的能量。因此，这是有理由遗传的mtDNA功能障碍是以低能量为特征的疾病的重要元素。这领域尚未广泛检验这一假设，但是在很大程度上是因为生物识别或我们用来估计核DNA影响的家庭模型与研究完全不相容 MTDNA由于其独特的特征和遗传模式（例如，mtDNA自我再现无性敏感，直接传输到母亲线下）。当前的R01试图开发，验证和测试一个利用这种单数mtDNA继承模式以估计的模型 mtDNA（MT2）的变异所解释的方差比例。我们怀疑表兄弟会是在这方面特别有用的亲戚。母系表亲，包括非常遥远的表亲分享几乎所有的mtdna。相比之下，父系表亲通常不会共享mtDNA。我们将利用母体和父亲线的这种差异来估计MT2。一旦开发了经过验证，我们将在〜480万个人的多代人的样本中运行此模型 4至17代深，已与每年更新的医学和重要记录相关联在过去的25年中出现了。分析将侧重于阿尔茨海默氏病（AD）和其他关键衰老的结局（糖尿病，自杀，帕金森氏病和寿命）。这样，提议 R01不仅应对AD的起源和相关衰老条件产生关键的新见解，但还将开发出新颖的方法来建立急需的贝叶斯“先验”来指导未来研究MTDNA的作用。