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

Noncoding Elements Shaping Brain Aging

塑造大脑老化的非编码元素

基本信息

批准号：
9980260
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980260
关键词：
Adult Affect 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 Cerebral Ischemia Child Clinical Cost of Illness 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 Lead 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 Reporting Research Resolution Rewards Role 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 comparative cost epigenetic marker feeding genetic regulatory protein genetic risk factor genome-wide analysis human disease improved in vivo innovation male mammalian genome metabolic phenotype mouse genetics neuroprotection novel therapeutic intervention 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.

项目总结在美国，每年与阿尔茨海默氏症相关的成本估计超过2430亿美元。相关因素尚不完全清楚，但新陈代谢过程起着重要作用。的确，肥胖和II型糖尿病是阿尔茨海默病的主要危险因素。更深入地了解其中涉及的机制是紧迫的，因为肥胖影响了17%的儿童，大约30%的美国成年人，特别是老年人。基因调控机制正在成为人类疾病的主要驱动力，但它们在人们对肥胖和阿尔茨海默氏症知之甚少。在这里，我们提出了一项研究，它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年龄相关的神经变性。我们的研究建立在我们最近发表在《细胞》杂志上的基础上报告(Ferris等人，2018)，在这些报告中，我们对加速的具有高度独特特征的物种中的区域(AR)，以定义哺乳动物的非编码元件临床上重要的表型。ARs是核苷酸显著增加的保守的基因组元件特定谱系中的替换，通常是由于选择性的影响。在一项未发表的研究中，我们建立在通过研究揭示哺乳动物肥胖和神经退行性变的调控因素冬眠者。冬眠者进化出新陈代谢和行为适应，导致可逆的肥胖表型。他们还进化出了防止大脑损伤的神经保护机制。我们确认了2370人哺乳动物基因组中在多个物种中经历平行加速进化的50bp元件独立进化的冬眠状态。我们称这些非编码元素为冬眠加速区 (ARS)，并发现了与人类肥胖和阿尔茨海默病风险基因相关的子集。我们的研究验证了冬眠者影响的保守元素接近肥胖和阿尔茨海默氏症的假设疾病风险基因是控制基因在不同组织和形状中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。我们的研究很有意义因为结果将定义重要的新的非编码机制，这些机制调节生物过程导致阿尔茨海默氏症。从长远来看，我们的结果有望帮助揭示基因的改良以及表观遗传生物标记物和治疗策略，以防止与年龄相关的肥胖和神经退化。