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慢性疾病的主要原因，包括2型糖尿病（T2D），心脏病发作，中风和癌症。只有一类药物，噻唑烷二酮（TZD），特别针对胰岛素抵抗通过激活脂肪细胞中的转录因子PPARG。虽然TZD已在临床上被证明有效预防T2D，心脏病发作和中风，严重的副作用限制了其临床使用。新的需要对抗胰岛素抵抗的治疗靶标。从理论上讲，基因表达变化引起通过TZD处理可以开采新的胰岛素敏感性，但TZD改变了表达数百个基因。这些必须通过功能投资来筛选因果效应而不是仅限相关或有毒的旁观者。标准的基于实验室的功能投资需要侵入性难以扩展的模型系统中的生理测量。即使潜在的胰岛素敏感性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类试验，这是另一个无法扩展的过程，通常会导致失败因为缺乏效率。但是，基因组序列最近在大型临床表征中的积累人口揭示自然已经以数百万自然的形式进行了无数的人类试验发生的，改变蛋白质的遗传变异几乎散布了基因组中的每个基因。关键释放这两个机会：1）从TZD治疗中识别新的候选基因； 2）利用自然评估治疗潜力的临床试验是高通量功能测定法。在这个应用，我们建议使用新开发的大量平行脂肪细胞分化/脂质以综合基因组方法的积累分析： AIM 1：快速分类TZD改变的基因，以使胰岛素敏化作用和 AIM 2：使用来自数据 100,000个测序个体。这项工作将产生对TZD的治疗作用的系统解剖来鉴定新型胰岛素灵敏度基因并直接评估人类调节功能的治疗潜力这些基因。