Molecular Mechanisms of Adverse Metabolic Events by Asparaginase.

天冬酰胺酶不良代谢事件的分子机制。

• 批准号: 8464939
• 负责人: Tracy G. Anthony
• 金额: $ 39.78万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-25 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464939
• 关键词: Acute Lymphocytic Leukemia; Address; Adolescent; Adverse event; Affect; Age; Amino Acids; Asparagine; Blood; Blood Coagulation Disorders; Blood coagulation; Cell Survival; Chemicals; Child; Childhood; Chronic; Clinical; Coagulation Process; Cytoplasm; Data; Development; Diagnosis; Drug Kinetics; Endoplasmic Reticulum; Ensure; Environment; Eukaryotic Initiation Factor-2; Event; Fatty Liver; Functional disorder; Gene Expression; Gene Expression Profile; Genetic Translation; Glutamine; Goals; Hepatic; Hepatocyte; Hepatotoxicity; Homeostasis; Hyperglycemia; Knowledge; Lead; Left; Liver; Liver Dysfunction; Liver Failure; Malignant Childhood Neoplasm; Metabolic; Methods; Molecular; Molecular Chaperones; Molecular Mechanisms of Action; Morbidity - disease rate; Mus; Outcome; Pancreas; Pancreatitis; Pathway interactions; Patients; Pharmacodynamics; Phosphorylation; Phosphotransferases; Plasma Proteins; Play; Prevention; Protein Biosynthesis; Protein Kinase; Proteins; Public Health; Publishing; Regimen; Research; Research Personnel; Risk; Role; Safety; Seizures; Serpins; Signal Transduction; Stress; Testing; Thromboembolism; Time; Tissues; Toxic effect; Treatment Protocols; United States; Wild Type Mouse; Work; age difference; asparaginase; base; cerebrovascular; endoplasmic reticulum stress; experience; improved; innovation; insight; liver function; liver metabolism; patient population; premature; prevent; protein aggregation; protein expression; protein folding; response; skills; therapy development; translation factor

DESCRIPTION (provided by applicant): Asparaginase is an integral part of the treatment for acute lymphoblastic leukemia, the most common childhood cancer. Asparaginase produces hepatotoxicity resulting in treatment-related metabolic complications that include fatty liver, reduced plasma proteins, and coagulation problems that lead to thromboembolism and cerebrovascular events. Our long-term goal is to increase the safety and efficacy of asparaginase. The objective of this proposal is to discover mechanisms by which asparaginase causes adverse metabolic effects. To accomplish this, we propose to identify key molecular events that modulate hepatic dysfunction by asparaginase. Our preliminary data demonstrate that asparaginase increases phosphorylation of the translation factor, eIF2, by GCN2. Deletion of GCN2 precludes adaptive responses to asparaginase and enhances endoplasmic reticulum (ER) stress, leading to induction of another eIF2 kinase called PKR-like ER- resident Kinase (PERK). The central hypothesis is that activation of eIF2 kinases prevent and/or mitigate hepatic dysfunction by asparaginase. We plan to test our hypothesis and accomplish the objective of this application by pursuing the following specific aims: Aim 1) Identify the role of GCN2 in liver during asparaginase treatment; Aim 2) Determine the role of PERK in liver during asparaginase treatment; Aim 3) Characterize age differences in eIF2 kinase signaling in liver by asparaginase. To accomplish the above aims, asparaginase will be administered to both wild-type mice and mice deleted for the eIF2 kinases, GCN2 and/or PERK. Time course analysis will focus on how modulation of eIF2 kinase signaling and activation of ER stress relates to development of liver dysfunction. In addition, asparaginase will be administered to mice of varying ages and key molecular and metabolic responses to asparaginase will be assessed. This proposal is innovative in that it seeks to identify the progression of molecular events that lead to liver dysfunction by asparaginase at different ages. The work proposed is significant as it will help identify pediatric patients at risk for adverse metabolic events by asparaginase during the developmental continuum. The results will also be used to develop and test new methods of prevention and/or treatment.

描述（由申请人提供）：天冬酰胺酶是急性淋巴细胞白血病治疗的组成部分，这是最常见的儿童癌症。天冬氨酸酶产生肝毒性，导致与治疗相关的代谢并发症，包括脂肪肝，减少血浆蛋白以及导致血栓栓塞和脑血管事件的凝结问题。我们的长期目标是提高天冬酰胺酶的安全性和功效。该建议的目的是发现天冬酰胺酶会引起不良代谢作用的机制。为此，我们建议确定通过天冬酰胺酶调节肝功能障碍的关键分子事件。我们的初步数据表明，天冬酰胺酶通过GCN2增加了翻译因子EIF2的磷酸化。 GCN2的缺失排除了对天冬酰胺酶的适应性反应并增强内质网（ER）应激，从而导致诱导另一种称为PKR样ER-居住的ER-常住激酶（PERK）的EIF2激酶。中心假设是EIF2激酶的激活预防和/或通过天冬酰胺酶减轻肝功能障碍。我们计划通过追求以下特定目的来检验我们的假设并实现该应用的目标：目标1）确定在天冬酰胺酶治疗期间GCN2在肝脏中的作用；目标2）确定在天冬酰胺酶处理过程中PERK在肝脏中的作用； AIM 3）表征天冬氨酸酶在肝脏中EIF2激酶信号传导中的年龄差异。为了实现上述目的，白云母酶将用于对野生型小鼠和为EIF2激酶（GCN2和/或PERK）删除的小鼠。时间课程分析将重点介绍EIF2激酶信号的调节和ER应力的激活与肝功能障碍的发展有关。此外，将评估天冬氨酸酶对不同年龄的小鼠以及对天冬酰胺酶的关键分子和代谢反应的施用。该提议具有创新性，因为它试图确定导致不同年龄段天冬氨酸酶导致肝功能障碍的分子事件的进展。提出的工作非常重要，因为它将有助于确定发育连续性期间天冬酰胺酶发生不良代谢事件风险的小儿患者。结果还将用于开发和测试新的预防和/或治疗方法。