Combining experiments of man and nature to target human insulin resistance

结合人与自然的实验来针对人类胰岛素抵抗

基本信息

批准号：
10316203
负责人：
Amit Majithia
金额：
$ 42.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-10 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316203
关键词：
Adipocytes Adipose tissue Alleles Biological Assay Biological Models Candidate Disease Gene Cardiovascular Diseases Cell physiology Cellular Assay Chronic Disease Clinical Clinical Research Clinical Trials Code Complement Conduct Clinical Trials Credentialing DNA Data Data Set Development Disease Dissection Dose Epidemic Exhibits Failure Fatty Liver Foundations Gene Expression Gene Expression Profiling General Population Genes Genetic Genetic Transcription Genetic Variation Genome Genomic approach Genotype Gold Human In Vitro Individual Insulin Insulin Resistance Investigation Laboratories Life Lipids Lipodystrophy Liver Failure Malignant Neoplasms Measurement Measures Metabolic Diseases Mining Modernization Mutagenesis Myocardial Infarction Nature Non-Insulin-Dependent Diabetes Mellitus PPARG gene PTEN gene Participant Persons Pharmaceutical Preparations Phenotype Physiological Population Process Proteins Reading Role Series Severity of illness Source Stroke Testing Therapeutic Therapeutic Effect Thiazolidinediones Tissue Sample Variant Work Writing activating transcription factor adipocyte differentiation base case control clinical efficacy clinical phenotype combat disorder risk drug development exome sequencing experimental study fatty liver disease gene discovery gene function gene synthesis genetic variant genome sequencing genome-wide genomic data high risk improved in vivo insulin sensitivity insulin sensitizing drugs loss of function man new therapeutic target novel prevent prospective resistance gene response side effect targeted treatment theories therapeutic candidate therapeutic development therapeutic gene therapeutic target transcriptome transcriptomics treatment response

项目摘要

Abstract Insulin resistance is a major cause of chronic diseases including type 2 diabetes (T2D), heart attacks, strokes and cancer. Only one class of medications, thiazolidinediones (TZDs), specifically targets insulin resistance primarily by activating the transcription factor PPARG in adipocytes. While TZDs have proven clinically effective in preventing T2D, heart attacks and strokes, serious side effects have limited their clinical use. New therapeutic targets to combat insulin resistance are needed. In theory, the gene expression changes caused by TZD-treatment could be mined for novel insulin-sensitizing effectors, but TZDs alter the expression of hundreds of genes. These must be sifted by functional investigation for causal effectors versus merely correlated or toxic bystanders. Standard laboratory-based functional investigation requires invasive physiological measurements in model systems that are difficult to scale. Even when a potential insulin sensitizing effector gene is validated in the lab, credentialing its relevance to human insulin sensitivity necessitates drug development and human trials, another poorly scalable process that usually results in failure for lack of efficacy. However, the recent accumulation of genome sequences in large, clinically characterized populations has revealed that nature has performed countless human trials in the form of millions of naturally occurring, protein-altering genetic variants scattered throughput almost every gene in the genome. The key to unlocking both these opportunities: 1) identifying novel candidate genes from TZD treatment and 2) leveraging nature’s clinical trials for assessing therapeutic potential, are high-throughput functional assays. In this application, we propose to utilize a newly developed massively parallel adipocyte differentiation/ lipid accumulation assay in an integrative genomic approach to: Aim 1: Rapidly sort TZD-altered genes for likelihood of being insulin sensitizing effectors and Aim 2: Credential already identified and novel candidates for therapeutic potential in humans using data from 100,000 sequenced individuals. This work will produce a systematic dissection of the therapeutic effect of TZDs to identify novel insulin sensitivity genes and directly assess the therapeutic potential of modulating function in humans for four of these genes.

抽象的胰岛素抵抗是导致 2 型糖尿病 (T2D)、心脏病、中风等慢性疾病的主要原因只有一类药物，即噻唑烷二酮类药物 (TZD)，专门针对胰岛素抵抗。主要是通过激活脂肪细胞中的转录因子 PPARG，而 TZD 已在临床上得到证实。可有效预防 T2D、心脏病和中风，但严重的副作用限制了其临床应用。理论上，需要治疗靶点来对抗胰岛素抵抗所引起的基因表达变化。通过 TZD 治疗可以挖掘新型胰岛素增敏效应器，但 TZD 会改变必须通过功能研究来筛选数百个基因，以寻找因果效应，而不是仅仅进行研究。标准的基于实验室的功能调查需要侵入性的或有毒的旁观者。即使使用潜在的胰岛素，模型系统中的生理测量也难以扩展。致敏效应基因在实验室中得到验证，证明其与人类胰岛素敏感性的相关性需要药物开发和人体试验，这是另一个可扩展性差的过程，通常会导致失败然而，最近大量的基因组序列积累，具有临床特征。人类已经揭示，大自然以数以百万计的自然试验的形式进行了无数的人类试验变异体、改变蛋白质的遗传分散通量几乎基因组中的每个基因。解锁这两个机会：1）从 TZD 治疗中识别新的候选基因，2）利用大自然评估治疗潜力的临床试验属于高通量功能测定。应用中，我们建议利用新开发的大规模并行脂肪细胞分化/脂质综合基因组方法中的积累测定：目标 1：快速分类 TZD 改变的基因，以确定其成为胰岛素增敏效应子的可能性和目标 2：利用来自以下数据的数据，已经确定了具有人类治疗潜力的证书和新候选者： 100,000 个已测序个体。这项工作将对 TZD 的治疗效果进行系统剖析，以确定新型胰岛素敏感性基因，并直接评估四种人类调节功能的治疗潜力这些基因。