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Mechanisms of Drug Induced Phospholipidosis

药物诱导磷脂沉积的机制

基本信息

批准号：
8665796
负责人：
JAMES ALAN SHAYMAN
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8665796
关键词：
Address Affect Alveolar Macrophages Amiodarone Amitriptyline Appearance Attention Azithromycin Basic Science Biological Assay Cell Line Cells Cellular biology Ceramides Charge Chemicals Chloroquine Chronic Clindamycin Clinical Clinical Research Complication Cultured Cells Development Disease Drug Approval Drug Prescriptions Drug Targeting Drug toxicity Drug usage Electrostatics Engineering Enzymes Fatty Acids Fluoxetine General Population Glycerophospholipids Grant Health Histology Imipramine In Vitro Inherited Inpatients Ketoconazole Knockout Mice Lead Lipids Lysosomal Storage Diseases Lysosomes Measures Membrane Lipids Metabolic Modeling Morbidity - disease rate Mus Mutate Mutation Names Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Phospholipase Phospholipase A2 Phospholipids Preclinical Drug Evaluation Predisposition Property Proteins Risk Role Scientist Secondary to Severities Single Nucleotide Polymorphism Susceptibility Gene Tamoxifen Testing Toxic effect Uncertainty United States Department of Veterans Affairs Veterans Work base burden of illness drug candidate drug development drug discovery drug mechanism enzyme mechanism enzyme substrate insight macrophage medical complication mortality novel patient population prevent programs public health relevance transacylation

项目摘要

DESCRIPTION (provided by applicant) Drug toxicities represent a significant disease burden in the ambulatory and inpatient settings. Many drug toxicities are idiopathic in presentation and severity and often result in significant morbidity and mortality for those affected. Drug-induced phospholipidosis is one such toxicity. Drug-induced phospholipidosis is manifest as the intra-lysosomal accumulation of glycerophospholipids in association with the chronic use of commonly used pharmaceuticals. Specific examples of agents that cause phospholipidosis include, but are not limited to, azithromycin, fluoxetine, amiodarone, chloroquine, imipramine, and ketoconazole. Ascertaining the significance of this complication has been problematic for clinicians, as well as scientists and regulatory agencies overseeing drug discovery and approval. This is due to a limited understanding of the mechanisms responsible for phospholipidosis and the lack of suitable models for its study. Lysosomal phospholipase A2 is a recently discovered and characterized phospholipase that hydrolyzes those phospholipids that accumulate secondary to drug-induced phospholipidosis. In addition, mice engineered to express an inactive form of lysosomal phospholipase A2 develop a phenotype that closely resembles the clinical manifestations of this disorder. Specifically, these mice develop lysosomal phospholipid accumulation most prominently within their alveolar macrophages. When normal alveolar macrophages are exposed to amiodarone and additional phospholipidosis associated drugs, in vitro, lysosomal phospholipase A2 activity is inhibited in concert with phospholipid accumulation. Based on these observations, the primary hypothesis to be tested is that drug-induced phospholipidosis is the consequence of inhibition of lysosomal phospholipase A2. This grant will test this hypothesis by use of a newly developed fluorometric assay for lysosomal phospholipase A2 activity and the use of knockout mice that are partially or totally deficient in lysosomal phospholipase A2 activity. Also included in this project are mechanistic studies on the role of electrostatic charge interactions between the lysosomal phospholipase A2 protein and lipid membranes that contain the substrates for the enzyme. Finally, the association between common mutations in the lysosomal phospholipase A2 gene and susceptibility to drug-induced phospholipidosis will be studied by the expression of the mutated protein in cell lines. If the inhibition of lysosomal phospholipase A2 is demonstrated to be a primary mechanism for drug-induced hospholipidosis, then these findings may serve as both the basis for screening drugs that may cause this complication as well as for the identification of patients who may be uniquely sensitive to this form of drug toxicity.

描述（由申请人提供）