Elucidation of Tissue-Specific Transcriptomic Profiles in Cardiometabolic Disease

心脏代谢疾病组织特异性转录组谱的阐明

• 批准号: 8827410
• 负责人: Mingyao Li
• 金额: $ 51.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-16 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827410
• 关键词: Address; Adipocytes; Adipose tissue; African American; Allelic Imbalance; Alternative Splicing; Atherosclerosis; Blood; Blood Cells; Cataloging; Catalogs; Cells; Clinical; Complex; Coupled; DNA; DNA Sequence; Data Set; Diet; Disease; Elements; Endotoxemia; Endotoxins; Epigenetic Process; Functional disorder; Funding; Gene Expression Profile; Genetic; Genetic Polymorphism; Genome; Genomics; Goals; Heritability; High-Throughput RNA Sequencing; Hip region structure; Human; Immune response; In Vitro; Individual; Inflammatory; Inflammatory Response; Inherited; Inpatients; Knowledge; Lipopolysaccharides; Metabolic; Metabolic Diseases; Modeling; National Heart, Lung, and Blood Institute; Natural Immunity; Nicotinic Acids; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Participant; Protein Isoforms; Protocols documentation; RNA; RNA Sequences; Recruitment Activity; Regulation; Role; Sampling; Signal Transduction; Source; Stem cells; TNFRSF5 gene; Tail; Therapeutic; Tissue Model; Tissues; Transcript; Translations; Untranslated RNA; Variant; Work; base; clinically relevant; epigenetic profiling; epigenetic regulation; epigenome; epigenomics; functional genomics; genome wide association study; human disease; human tissue; in vitro Model; in vivo; induced pluripotent stem cell; innovation; insight; monocyte; novel; research study; response; stem cell technology; therapeutic target; tissue resource; tool; trait; transcriptome sequencing; transcriptomics

DESCRIPTION (provided by applicant): Recent genome wide association studies (GWAS) have provided increased insight into the genetic basis of complex cardio-metabolic diseases (CMD) including type-2 diabetes and atherosclerotic cardiovascular diseases. Such discoveries, however, only explain a small proportion of the heritability suggesting genetic influences other than common DNA variation need to be considered. Knowledge of the transcriptome is essential for a more complete understanding of the inherited functional elements of the genome. The advent of high-throughput RNA sequencing (RNA-seq), including our work, demonstrates the existence of a far greater transcriptomic complexity and diversity than previously catalogued. The host response to endotoxin (LPS) provides fundamental insights into transcriptomic regulation of innate immunity while also serving as a model for inflammatory CMD. In the Genetics of Evoked-Responses to Niacin and Endotoxemia (GENE) study, we recruited healthy individuals (N=286) to an inpatient protocol and collected blood and adipose samples before and after administration of endotoxin (1ng/kg intravenously). Here, we propose to perform monocyte and adipose transcriptomic and epigenomic profiling during experimental human endotoxemia in order to discover tissue-specific mechanisms of human disease. In Aim 1, we will utilize the clinical-inflammatory response in GENE participants to identify extreme "low" (~<5%PC) and "high" (~>95%PC) responders in order to detect endotoxin-induced transcriptomic responses of greatest clinical relevance. In Aim 2, we will replicate LPS- induced transcriptomic changes, define the epigenetic regulation, and pursue clinical translation of replicated findings. In Aim 3, we hypothesize that basal and endotoxin-evoked epigenome/transcriptome response in differentiated human induced pluripotent stem cells (hiPSC) from GENE participants will resemble that in primary cells and tissues. This proposal combines unique clinical resources, tissue-specific transcriptomics, and ex vivo profiling of hiPSC in order to identify heritable contribution to CMD, discover novel disease mechanisms and therapeutic opportunities, and advance innovation in the study of human disease.

描述（由申请人提供）：最近的基因组广泛关联研究（GWAS）为复杂的心脏代谢疾病（CMD）（包括2型糖尿病和动脉粥样硬化性心血管疾病）的遗传基础提供了越来越多的见解。然而，这种发现仅解释了一小部分遗传力表明遗传影响以外的其他DNA变异需要考虑。对转录组的了解对于对基因组的遗传功能元素的更完整理解至关重要。包括我们的工作在内的高通量RNA测序（RNA-Seq）的出现表明，与以前分类相比，具有更大的转录组复杂性和多样性的存在。宿主对内毒素（LPS）的反应提供了对先天免疫转录组调节的基本见解，同时也是炎症性CMD的模型。在对烟酸和内毒素（Gene）研究的诱发响应遗传学中，我们将健康个体（n = 286）招募到住院方案中，并在施用内毒素之前和之后收集了血液和脂肪样品（静脉注射1NG/kg）。在这里，我们建议在实验性人内毒素血症期间执行单核细胞和脂肪转录组和表观基因组分析，以发现人类疾病的组织特异性机制。在AIM 1中，我们将利用基因参与者中的临床炎症反应来确定极端的“低”（〜5％PC）和“高”（〜95％PC）响应者，以检测内毒素诱导的最大临床相关性的转录组反应。在AIM 2中，我们将复制LPS诱导的转录组变化，定义表观遗传调节并追求复制发现的临床翻译。在AIM 3中，我们假设在分化的人类诱导的多能干细胞（HIPSC）中，基因和内毒素诱发的表观基因组/转录组反应将与原代细胞和组织中相似。该提案结合了HIPSC的独特临床资源，特定的转录组学和离体分析，以确定对CMD的可遗传贡献，发现新型疾病机制和治疗机会，并在人类疾病研究中提高创新。