Investigating the impact of genetic variation on ER stress response and disease

研究遗传变异对内质网应激反应和疾病的影响

• 批准号: 9381654
• 负责人: Clement Chow
• 金额: $ 37.92万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381654
• 关键词: Architecture; Area; Cell Death; Cells; Complex; Development; Diabetes Mellitus; Disease; Disease Outcome; Drosophila genus; Endoplasmic Reticulum; Genes; Genetic; Genetic Transcription; Genetic Variation; Goals; Individual; Laboratories; Left; Modification; Mus; Mutation; Nature; Neurodegenerative Disorders; Organelles; Outcome; Pathogenicity; Pathway interactions; Pharmacology; Phenotype; Play; Proteins; Rare Diseases; Role; Testing; Variant; biological adaptation to stress; design; disease-causing mutation; endoplasmic reticulum stress; genetic element; genetic variant; genome-wide; individual patient; misfolded protein; personalized medicine; response; tool

PROJECT SUMMARY One of the biggest challenges to treating disease is the fact that individuals carrying the same pathogenic mutation can present with different disease outcomes. It is increasingly recognized that this variation can arise, in large part, due to genetic background differences of each individual. In some cases, this genetic variation appears to be more important than the underlying causative mutation. In order to truly understand how genetic variation interacts with disease causing mutations, laboratory disease studies need to take into account genetic variation. We are applying this approach to the endoplasmic reticulum (ER) stress response. The ER is a large organelle responsible for the synthesis, maturation, and delivery of proteins responsible for a variety of essential functions. ER stress occurs when misfolded proteins accumulate in the lumen of the ER. If left unresolved, cell death occurs, followed by disease. The cell responds to ER stress with the unfolded protein response (UPR). The UPR initiates a very large transcriptional response that is aimed at clearing misfolded proteins from the ER. ER stress is an important component to a number of common and rare diseases, including diabetes and neurodegenerative disorders. Importantly, many studies are now showing that pharmacological or genetic modification of the ER stress response can alter the outcome of many diseases. We hypothesize that genetic variation in the ER stress response is an important contributor to variability in disease. In order to test this, we need to understand the nature and mechanism by which ER stress varies among individuals. We utilize a number of tools in mouse and Drosophila to understand the role of genetic variation. We have recently demonstrated that the ER stress response and outcomes of disease of the ER stress response are incredibly variable and complex across individuals and genetic backgrounds. Our long term goal is to understand how genes and genetic variants interact to produce such a variable response. To do this, we will focus on two areas in this proposal: 1) Uncover the genetic architecture underlying genetic variation of the ER stress response in the mouse. We propose a number of studies aimed at understanding this at the genome-wide level, gene level, and SNP level; and 2) understand how genetic modifiers influence the phenotypic outcome of diseases of the ER stress response. Knowing how genetic variation impacts a critical disease-relevant pathway, like ER stress, will assist in designing personalized therapies that might better treat the individual patient.

项目摘要 治疗疾病的最大挑战之一是， 致病性突变可导致不同的疾病结果。人们日益认识 这种变异很大程度上是由于每个个体的遗传背景差异造成的。 在某些情况下，这种遗传变异似乎比潜在的致病因素更重要 突变为了真正了解遗传变异如何与疾病发生相互作用， 突变，实验室疾病研究需要考虑遗传变异。我们正在申请 这种方法的内质网（ER）应激反应。ER是一个巨大的细胞器 负责合成、成熟和递送蛋白质，这些蛋白质负责各种 基本功能。当错误折叠的蛋白质积聚在细胞腔中时， 儿如果不解决，就会发生细胞死亡，然后是疾病。细胞对内质网应激的反应是 未折叠蛋白反应（Unfolded protein response，UPR）UPR启动了一个非常大的转录反应， 旨在清除内质网中错误折叠的蛋白质。ER应力是一个重要的组成部分， 一些常见和罕见疾病，包括糖尿病和神经退行性疾病。 重要的是，现在许多研究表明，药物或遗传修饰的 ER应激反应可以改变许多疾病的结局。我们假设基因 ER应激反应的变化是疾病变异性的重要因素。为了 为了验证这一点，我们需要了解ER应力在不同的环境中变化的性质和机制。 个体我们在小鼠和果蝇中使用了一些工具来了解遗传的作用。 变化量我们最近已经证明，ER应激反应和疾病的结果， 的ER应激反应是令人难以置信的变化和复杂的个体和遗传 背景我们的长期目标是了解基因和遗传变异如何相互作用， 产生这样一种多变的反应。为此，我们将在本提案中重点关注两个方面：1） 揭示了遗传结构潜在的遗传变异的内质网应激反应， 老鼠.我们提出了一些旨在在全基因组水平上理解这一点的研究， 基因水平和SNP水平; 2）了解遗传修饰剂如何影响表型 ER应激反应疾病的结局。了解遗传变异如何影响一个关键的 疾病相关途径，如ER应激，将有助于设计个性化治疗， 可以更好地治疗个体患者。