Noncoding Elements Shaping Brain Aging

塑造大脑老化的非编码元素

基本信息

批准号：
10619648
负责人：
Chris Gregg
金额：
$ 38.13万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10619648
关键词：
Acceleration Adult Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease risk Anxiety Base Pairing Behavior Behavioral Binding Sites Bioinformatics Biological Markers Biological Process Brain Diseases Brain Injuries Brain region CRISPR/Cas technology Cells Child Clinical Collaborations Data Development Disease Elderly Elements Embryo Energy Metabolism Enhancers Epigenetic Process Evolution Fatty acid glycerol esters Feeding behaviors Female Frequencies Gene Expression Gene Expression Regulation Genes Genetic Genetic Markers Genetic Risk Genome Genomics Goals Hibernation Human Insulin Resistance Introns Knock-out Knockout Mice Learning Link Longevity Magnetic Resonance Imaging Medical Metabolic Metabolic Control Metabolism Mus Nerve Degeneration Non-Insulin-Dependent Diabetes Mellitus Nucleotides Obesity Paper Pattern Phenotype Play Prevention strategy Process Public Health Publications Regulator Genes Regulatory Element Reporter Reporter Genes Reporting Research Resolution Rewards Role Seasons Shapes Site System Testing Therapeutic Tissues Transgenic Organisms United States Untranslated RNA Variant age related age related neurodegeneration aged aging brain behavioral phenotyping brain morphology brain shape brain tissue cerebral atrophy cerebral ischemic injury comparative cost epigenetic marker feeding genetic regulatory protein genetic risk factor genome-wide genome-wide analysis human disease improved in vivo innovation male mammalian genome metabolic phenotype mouse genetics neuroprotection novel therapeutic intervention obesity prevention obesity risk obesogenic prevent risk variant screening therapeutic target trait treatment strategy

项目摘要

PROJECT SUMMARY The costs associated with Alzheimer's disease are estimated at over $243 billion annually in the United States. The factors involved are not fully understood, but metabolic processes play an important role. Indeed, obesity and type II diabetes are major risk factors for Alzheimer's disease. Gaining a deeper understanding of the mechanisms involved is urgent, because obesity affects 17% of children, ~30% of US adults and especially the elderly. Gene regulatory mechanisms are emerging as major drivers of human disease, but their roles in obesity and Alzheimer's disease are poorly understood. Here, we propose a study that will uncover new and important noncoding elements and gene regulatory mechanisms in the genome that underlie mammalian obesity and age-related neurodegeneration. Our study builds on our recent publication in Cell Reports (Ferris et al., 2018), in which we performed a comparative genome-wide analysis of accelerated regions (ARs) in species with highly distinctive traits to define mammalian noncoding elements that shape clinically important phenotypes. ARs are conserved genomic elements with significantly increased nucleotide substitutions in a specific lineage, typically due to selective effects. In an unpublished study, we built on our approach to uncover regulatory elements shaping mammalian obesity and neurodegeneration by studying hibernators. Hibernators evolved metabolic and behavioral adaptations that resulted in a reversible obesogenic phenotype. They also evolved neuroprotective mechanisms that prevent brain damage. We identified 2370 50bp elements in the mammalian genome that underwent parallel accelerated evolution in multiple species that independently evolved hibernation. We call these noncoding elements hibernator accelerated regions (ARs) and found a subset associated with risk loci for human obesity and Alzheimer's disease. Our study tests the hypothesis that the conserved elements impacted by hibernator ARs near obesity and Alzheimer's disease risk genes are critical regulatory elements that control gene expression in different tissues and shape obesogenic behaviors, metabolic activity and age-related neurodegeneration. Our study is significant because the results will define important new noncoding mechanisms that regulate biological processes contributing to Alzheimer's disease. In the long-term, our results are expected to help reveal improved genetic and epigenetic biomarkers and therapeutic strategies to prevent age-related obesity and neurodegeneration.

项目概要在美国，每年与阿尔茨海默病相关的费用估计超过 2,430 亿美元。所涉及的因素尚不完全清楚，但代谢过程起着重要作用。确实，肥胖和II型糖尿病是阿尔茨海默病的主要危险因素。获得更深入的了解所涉及的机制迫在眉睫，因为肥胖影响着 17% 的儿童、约 30% 的美国成年人，尤其是老年。基因调控机制正在成为人类疾病的主要驱动因素，但它们在人们对肥胖和阿尔茨海默病知之甚少。在这里，我们提出了一项研究，该研究将揭示新的以及基因组中重要的非编码元件和基因调控机制哺乳动物肥胖和与年龄相关的神经变性。我们的研究建立在我们最近在《细胞》杂志上发表的文章的基础上报告（Ferris 等人，2018），其中我们对加速的全基因组范围进行了比较分析具有高度独特性状的物种中的区域（AR）来定义塑造哺乳动物非编码元件临床上重要的表型。 AR 是保守的基因组元件，核苷酸显着增加特定谱系中的替代，通常是由于选择性效应。在一项未发表的研究中，我们建立在通过研究揭示影响哺乳动物肥胖和神经退行性变的调控因素的方法冬眠者。冬眠者进化出代谢和行为适应，导致可逆的肥胖表型。它们还进化出了防止脑损伤的神经保护机制。我们确定了 2370 哺乳动物基因组中的 50bp 元件在多个物种中经历了并行加速进化独立进化出冬眠。我们将这些非编码元素称为休眠加速区域（AR）并发现了与人类肥胖和阿尔茨海默病风险位点相关的子集。我们的研究检验了以下假设：肥胖和阿尔茨海默病附近的冬眠 AR 影响的保守元件疾病风险基因是控制不同组织和形状中基因表达的关键调控元件肥胖行为、代谢活动和与年龄相关的神经变性。我们的研究意义重大因为结果将定义调节生物过程的重要的新非编码机制导致阿尔茨海默病。从长远来看，我们的结果预计将有助于揭示改善的遗传以及表观遗传生物标志物和预防与年龄相关的肥胖和神经退行性疾病的治疗策略。