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：
8586243
负责人：
Kirsten C Sadler Edepli
金额：
$ 36.73万
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 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8586243
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 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 Metric 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 health economics in vivo in vivo Model insight liver transplantation loss of function meter novel prevent protein folding public health relevance response therapy development tool 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）：估计有超过 1 亿美国人患有脂肪肝疾病 (FLD)。这是糖尿病、病毒性肝炎和艾滋病毒感染发病率总和的五倍。 FLD 的初始阶段可以通过改变生活方式来治愈。然而，即使目前 FLD 患者中的一小部分进展到晚期，仅对这些患者的管理就会使诊所、肝移植等候名单和医疗保健预算不堪重负。迫切需要了解导致这种疾病的第一步，即肝细胞中脂质积累（脂肪变性）的细胞途径，以便设计针对这些途径的有效疗法。此外，需要体内模型来测试候选药物。我们利用斑马鱼幼虫来研究导致脂肪变性的基因和途径。其中一个途径是未折叠蛋白反应（UPR）的激活，它可以作为分泌途径中压力的计量表。我们开发了几种诱导斑马鱼幼虫脂肪变性的方法，发现所有这些方法都发生 UPR 激活。使用斑马鱼研究 UPR 与脂肪变性之间的联系的优点包括相对快速且廉价的遗传方法、大样本量、小动物尺寸以及与人类的遗传同源性。此外，斑马鱼脂肪肝的组织病理学与患者中看到的非常相似，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，虽然强大的 UPR 通常会导致脂肪变性，但在适度的 UPR 不会，相反，可以防止它。 UPR 非常复杂，现在很明显，对 UPR 激活的孤立指标进行分析不足以了解 URP 激活如何导致或减少脂肪变性。我们将通过将多个 UPR 激活指标集成到一个系统中来解决这个问题，以了解它们与脂肪变性结果的关系。目标 1 中的系统生物学方法将使我们能够生成分子指标的签名，识别与脂肪变性相关的应激 UPR 以及防止脂肪变性的适应性 UPR。一旦我们了解了 UPR 的复杂性和动态性质，我们就可以用它来确定当关键 UPR 参与者之一 Atf6 耗尽时，慢性 UPR 激活引起的脂肪变性如何减少，而急性 UPR 激活引起的脂肪变性随着 Atf6 耗尽而恶化。在目标 2 中，假设在慢性 UPR 激活中，Atf6 耗竭会降低“应激 UPR”。在目标 3 中，我们将分析 Atf6 耗尽是否会剥夺肝细胞完全储备的蛋白质折叠能力，从而加剧急性损伤引起的应激性 UPR。这项工作将提供有价值的信息，阐明各个 UPR 成分可用于治疗不同病因引起的脂肪肝疾病的机制。