The impact of the unfolded protein responses on steatosis

未折叠蛋白反应对脂肪变性的影响

基本信息

批准号：
8775184
负责人：
Kirsten C Sadler Edepli
金额：
$ 36.21万
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：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8775184
关键词：
Acute Address Alcohols American Animals Apoptosis Award Biological Brefeldin A Budgets Cells Chronic Chronic stress Clinic Complex Conflict (Psychology)Data Diabetes Mellitus Disease Endoplasmic Reticulum Ensure Etiology Exposure to Fatty Liver Funding Gene Expression Gene Targeting Genes Genetic Goals Golgi Apparatus HIV Infections Health Healthcare Healthcare Systems Hepatocyte Human Immunoblotting Incidence Individual Injection of therapeutic agent Larva Lead Life Style Link Lipids Liver diseases Machine Learning Measures Mediating Mediator of activation protein Metabolic Modeling Molecular Profiling Mutation Nature Nuclear Outcome Pathway interactions Patients Positioning Attribute Protein Glycosylation Protein Secretion Proteins Public Health Quality Control RNA Sequences RNA Splicing Recovery Regression Analysis Role Sample Size Staging Stress Structure System Systems Biology Testing Time Transgenic Organisms Tunicamycin Viral hepatitis Waiting Lists Work Zebrafish acute stress alcohol exposure binge drinking design drug candidate economic impact effective therapy endoplasmic reticulum stress genetic approach health economics in vivo in vivo Model insight liver transplantation loss of function meter novel prevent protein folding response therapy development tool transcriptome sequencing treatment strategy

项目摘要

DESCRIPTION (provided by applicant): More than 100 million Americans are estimated to have fatty liver disease (FLD). This is five times the combined incidence of diabetes, viral hepatitis and HIV infection. The initial stages of FLD can be cured with lifestyle changes. However, if even a small percentage of current FLD patients progress to advanced stages, the management of these patients alone will overwhelm clinics, liver transplant waiting lists and health care budgets. There is an urgent need to understand the cellular pathways that contribute to the first step of this disease, accumulation of lipid in hepatocytes (steatosis), so s to design effective therapies to target these pathways. Moreover, in vivo models are needed to test candidate drugs. We use zebrafish larvae to study the genes and pathways that lead to steatosis. One such pathway is the activation of the unfolded protein response (UPR) which serves as a meter for stress in the secretory pathway. We developed several means of inducing steatosis in zebrafish larvae discovered that UPR activation occurs in all of these. The advantage of using zebrafish for studying the link between the UPR and steatosis include the relatively rapid and inexpensive genetic approaches, large sample size, small animal size and genetic homology to humans. Also, the histopatholgy of fatty liver in zebrafish is very similar to what is seen in patients and it is likely that many of the same pathophysiological mechanisms will contribute to this disease. We found that while a robust UPR typically causes steatosis, in a moderate UPR does not, and instead, protects against it. The UPR is highly complex, and it is now clear that analysis of isolated metrics of UPR activation is not sufficient to understand how URP activation can alternatively cause or reduce steatosis. We will address this by integrating multiple metrics UPR activation into a system in order to understand their relationships to the outcome of steatosis. This systems biology approach in Aim 1 will allow us to generate a signature of molecular metrics that identify the stressed UPR that is associated with steatosis and the adaptive UPR that protects against it. Once we understand the complex and dynamic nature of the UPR then we can use this to determine how steatosis caused by chronic UPR activation is reduced when one of the key UPR players, Atf6, is depleted whereas steatosis caused by acute UPR activation worsens with Atf6 depletion. In Aim 2 the hypothesis that in chronic UPR activation, Atf6 depletion dials down a 'stressed UPR'. In Aim 3, we will analyze whether Atf6 depletion deprives hepatocytes of the complete reserve of protein folding capacity, accentuating a stressed UPR caused by an acute insult. This work will provide valuable information elucidating the mechanism by which individual UPR components may serve to treat fatty liver disease caused by different etiologies.

描述（由申请人提供）：估计有1亿美国人患有脂肪肝病（FLD）。这是糖尿病，病毒肝炎和HIV感染的综合发生率的五倍。 FLD的初始阶段可以通过改变生活方式来治愈。但是，即使当前的FLD患者中，即使有一小部分患者进入高级阶段，仅这些患者的管理就会压倒诊所，肝移植等待名单和医疗保健预算。迫切需要了解导致该疾病第一步的细胞途径，脂质在肝细胞中的积累（Steteatosis）的积累，因此S设计有效的疗法以靶向这些途径。此外，需要体内模型来测试候选药物。我们使用斑马鱼幼虫来研究导致脂肪变性的基因和途径。这样的途径之一是展开的蛋白质反应（UPR）的激活，该反应是分泌途径中应力的仪表。我们开发了几种在斑马鱼幼虫中诱导脂肪变性的方法，发现所有这些都发生了UPR激活。使用斑马鱼研究UPR和脂肪变性之间的联系的优点包括相对较快且廉价的遗传方法，大样本量，小动物大小和与人类的遗传同源性。同样，斑马鱼中脂肪肝的组织病态与患者相似，并且许多相同的病理生理机制可能会导致这种疾病。我们发现，尽管强大的UPR通常会引起脂肪变性，但在中等UPR不会，而是可以防止它。 UPR非常复杂，现在很明显，对UPR激活的孤立指标的分析不足以了解URP激活如何替代引起或减少脂肪变性。我们将通过将多个指标UPR激活整合到系统中来解决这一问题，以了解它们与脂肪变性结果的关系。 AIM 1中的这种系统生物学方法将使我们能够生成分子指标的签名，这些签名识别与脂肪变性相关的压力UPR和保护脂肪的自适应UPR。一旦我们了解了UPR的复杂而动态的性质，我们就可以使用它来确定当慢性UPR激活引起的脂肪变性是如何减少慢性UPR激活时，当一个关键的UPR播放器ATF6耗尽时，而急性UPR激活引起的脂肪变性会导致ATF6 DEDETION降低。。在AIM 2中，假设在慢性UPR激活中，ATF6耗尽拨号降低了“压力UPR”。在AIM 3中，我们将分析ATF6耗竭是否剥夺了蛋白质折叠能力完全储备的肝细胞，从而突出了由急性侮辱引起的压力UPR。这项工作将提供有价值的信息，阐明单个UPR组件可以用来治疗不同病因引起的脂肪肝病的机制。