The impact of the unfolded protein responses on steatosis

未折叠蛋白反应对脂肪变性的影响

• 批准号: 8438156
• 负责人: Kirsten C Sadler Edepli
• 金额: $ 37.37万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/8438156
• 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

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（FLD）。这是糖尿病、病毒性肝炎和艾滋病毒感染综合发病率的五倍。FLD的初始阶段可以通过改变生活方式来治愈。然而，即使目前的FLD患者中有一小部分进展到晚期，仅对这些患者的管理将使诊所、肝移植等待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，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。我们使用斑马鱼幼虫来研究导致脂肪变性的基因和途径。一种这样的途径是未折叠蛋白反应（UPR）的激活，其充当分泌途径中的应激的计量器。我们开发了几种诱导斑马鱼幼虫脂肪变性的方法，发现UPR激活发生在所有这些。使用斑马鱼研究UPR与脂肪变性之间联系的优势包括相对快速且廉价的遗传方法、大样本量、小动物体积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观察到的非常相似，并且很可能许多相同的病理生理学机制将导致这种疾病。 我们发现，虽然一个强大的UPR通常会导致脂肪变性，在一个 UPR是高度复杂的，并且现在清楚的是，对UPR激活的孤立度量的分析不足以理解URP激活如何可以替代地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。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，该分子指标识别与脂肪变性相关的应激UPR和保护其免受其影响的适应性UPR。一旦我们了解了UPR的复杂性和动态性质，那么我们就可以使用它来确定当UPR的关键参与者之一Atf 6，而由急性UPR激活引起的脂肪变性伴随Atf6耗尽。在目标2中，假设在慢性UPR激活中，Atf 6耗尽会降低“应激UPR”。在目标3中，我们将分析Atf6耗竭是否剥夺了肝细胞的蛋白质折叠能力的完全储备，加重了由急性损伤引起的应激UPR。这项工作将提供有价值的信息，阐明个别UPR成分可能有助于治疗不同病因引起的脂肪肝疾病的机制。