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Human tissue specific age-related gene expression changes, their genetic regulations and the link to human diseases

人体组织特异性年龄相关基因表达变化、其遗传调控以及与人类疾病的联系

基本信息

批准号：
10319943
负责人：
Zhidong Tu
金额：
$ 37.07万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319943
关键词：
Address Age Aging Animal Model Animals Atlases Automobile Driving Biological Biological Assay Biological Models Biology of Aging Cell model Clustered Regularly Interspaced Short Palindromic Repeats Communities Data Data Set Disease Economics Engineering Ethics Etiology Evaluation Failure Female Gene Expression Gene Expression Alteration Gene Expression Profile Gene Expression Regulation Genes Genetic Genetic Risk Genomics Genotype Genotype-Tissue Expression Project Human Human Genetics Human body Intervention Link Longevity Names Pathway interactions Pattern Pharmaceutical Preparations Population Portraits Publishing Regulation Reporter Research Research Personnel Resources Sample Size Savings Sex Differences Speed System Testing Time Tissues Translational Research United States National Institutes of Health Validation Variant Work age related aging gene anti aging causal variant comorbidity cost epigenomics experimental study functional outcomes genetic variant genomic data healthspan healthy aging human data human disease human model human tissue innovation male novel sex transcription factor transcriptome transcriptomics

项目摘要

Project Summary Understanding human aging requires us to perform experiments directly with human. This can be challenging due to ethical barriers, high cost, long human lifespan and several other factors. On the other hand, a deluge of human genomic data have emerged and some of them have outstanding potentials to be repositioned for aging research. Leveraging existing human data for aging research provides an economically efficient, time- saving solution to overcome the many obstacles associated with human experiments. We propose to go deep in analyzing a very unique and unprecedented large scale human genomic dataset for aging research. This dataset as generated from GTEx (Genotype of Tissue Expression) project represents a rare opportunity for studying human aging gene expressions and genetics at multi-tissue level. We propose to work on four specific aims: first, we will define human aging gene expression signatures in more than 40 tissue types. For many tissues, this is the first time to reveal their aging gene expression change patterns. We will also investigate disease and sex influence on these aging gene expression and find conserved aging mechanisms from model organisms to human. Second, early studies have shown that different parts of human body age at different rates, but it is unknown if the biological ages of different tissues are under higher order coordination. Our work is to investigate on this topic to confirm our previous finding on the coordinated aging among tissues. We will also test if tissue co-aging correlates with disease comorbidity. Third, we will look into the genetic regulation on age-related gene expression in various tissues. We will test if genetic variants associated with aging gene expression could also be associated with human longevity or age-related diseases. Fourth, we will select top variants and experimentally validate the causal regulation on gene expression. We believe all these questions are important for human aging research; the answers to these questions will significantly help us to better understand human aging and help translational research.

项目摘要了解人类的衰老需要我们直接在人类身上进行实验。这可能是具有挑战性的由于道德障碍、成本高、人类寿命长等几个因素。另一方面，洪水泛滥人类基因组数据已经出现，其中一些数据具有值得重新定位的突出潜力老龄化研究。利用现有的人类数据进行老龄化研究提供了经济高效的时间- 节省解决方案，以克服与人体实验相关的许多障碍。我们建议深入研究在分析一个非常独特和史无前例的大规模人类基因组数据集以进行衰老研究时。这由GTEx(组织表达的基因类型)项目生成的数据集代表着在多组织水平上研究人类衰老基因的表达和遗传学。我们建议就四个具体问题开展工作目的：首先，我们将定义人类衰老基因在40多种组织类型中的表达特征。对许多人来说组织中，这是首次揭示其衰老基因表达的变化模式。我们还将调查疾病和性别对这些衰老基因表达的影响及从模型中寻找保守的衰老机制生物对人类的影响。第二，早期的研究表明，人体不同部位的年龄不同但尚不清楚不同组织的生物年龄是否处于更高级别的配位下。我们的工作就是研究这一主题，以证实我们之前关于组织之间协调衰老的发现。我们会还要测试组织共同老化是否与疾病共病相关。第三，我们将研究基因调控对年龄相关基因在不同组织中的表达。我们将测试基因变异是否与衰老基因有关表达也可能与人类长寿或与年龄相关的疾病有关。第四，我们将选择TOP 并从实验上验证了基因表达的因果调控。我们相信所有这些问题对人类衰老研究很重要；这些问题的答案将极大地帮助我们更好地了解人类衰老并帮助进行翻译研究。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Integration of transcriptomes of senescent cell models with multi-tissue patient samples reveals reduced COL6A3 as an inducer of senescence.

衰老细胞模型的转录组与多组织患者样本的整合揭示了 COL6A3 作为衰老诱导剂的减少。

DOI：
10.1016/j.celrep.2023.113371
发表时间：
2023
期刊：
Cell reports
影响因子：
8.8
作者：
Savić,Radoslav;Yang,Jialiang;Koplev,Simon;An,MahruC;Patel,PriyankaL;O'Brien,RobertN;Dubose,BrittanyN;Dodatko,Tetyana;Rogatsky,Eduard;Sukhavasi,Katyayani;Ermel,Raili;Ruusalepp,Arno;Houten,SanderM;Kovacic,JasonC;Stewart,An
通讯作者：
Stewart,An

A Compendium of Age-Related PheWAS and GWAS Traits for Human Genetic Association Studies, Their Networks and Genetic Correlations.

DOI：
10.3389/fgene.2021.680560
发表时间：
2021
期刊：
Frontiers in genetics
影响因子：
3.7
作者：
Kim SS;Hudgins AD;Gonzalez B;Milman S;Barzilai N;Vijg J;Tu Z;Suh Y
通讯作者：
Suh Y

Genetic signature of human longevity in PKC and NF-κB signaling.

DOI：
10.1111/acel.13362
发表时间：
2021-07
期刊：
Aging cell
影响因子：
7.8
作者：
Ryu S;Han J;Norden-Krichmar TM;Zhang Q;Lee S;Zhang Z;Atzmon G;Niedernhofer LJ;Robbins PD;Barzilai N;Schork NJ;Suh Y
通讯作者：
Suh Y

Molecular differences in brain regional vulnerability to aging between males and females.