CELLULAR MECHANISMS OF DRUG REACTIONS IN SCHIZOPHRENIA

精神分裂症药物反应的细胞机制

• 批准号: 2635493
• 负责人: EDMOND J YUNIS
• 金额: $ 16.67万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2635493
• 关键词: Jewish; cell death; clinical research; clozapine; drug adverse effect; genetic markers; genetic polymorphism; granulocytopenia; histocompatibility typing; human subject; immunogenetics; major histocompatibility complex; mental disorder chemotherapy; neutrophil; pharmacogenetics; psychopharmacology; schizophrenia; tumor necrosis factor alpha

DESCRIPTION (Adapted from applicant's abstract): There are different HLA associations in patients with clozapine-induced agranulocytosis (CA): in Jewish patients, HLA-B38, DR4 (DRB1*0402, DQB1*0302, DQA1*0301, DPB1*0401), HSP70 9.0-A, and in non-Jewish patients, HLA-DR2 (DRB1*1602, DQB1*0502, DQA1*0102), HSP70 9.0-A, HLA-B44, DR7 (DRB1*0701, DQB1*0202, DQB1*0201), HSP70 9.0-A. The haplotypes HLA-B8, DR3 (DRB1*0301, DQB1*0201, DQA1*0501, DPB1*0401), HSP70 8.5-C and HLA-B44, DR4 (DRB1*0401, DQB1*0301, DQA1*0301), HSP70 9.0-A are associated with protection. Preliminary studies suggest that common variants of non-HLA genes (TNF DNA constellations; a,b,c,d,e microsatellites, n intron of TNFB and -308 of promoter region of TNFa) (given in the gene order b,a,n,c, -308, e,d) within the major histocompatibility complex (MHC) are associated with the HLA CA markers. Also, clozapine and its metabolites can produce an increase of cytotoxicity or apoptosis of neutrophils. The induction of cell death of neutrophils by clozapine and its metabolites was significantly less in a homozygous HLA-B8, DR3, TNF-3, 2, 1, 1, 2, 3, 1 (associated with resistance to CA) than in HLA-B7, DR2, TNF-4 11, 2, 1, 1, 3, 3, 1 or in homozygous HLA-B38, DR4, TNF 4, 10, 2, 1, 1, 3, 3, individuals (associated with susceptibility to CA). Therefore, non-HLA MHC markers may underlie the hematologic complications of CA in patients with schizophrenia. This project has the following specific aims: 1) typing non-schizophrenic individuals who are a) homozygous or heterozygous for carrying different extended HLA haplotypes and b) homozygous or heterozygous for TNF constellations that may or may not be part of HLA extended haplotypes; 2) typing of CA patients of Jewish and non-Jewish ancestry to characterize TNF DNA constellation polymorphisms in order to identify common markers of CA in different ethnic groups; 3) the induction of cell death of neutrophils in the presence or absence of clozapine and its metabolites in selected homozygous and heterozygous individuals of different MHC haplotypes. The study of TNF polymorphism in relation to the physiology of cells in the presence of drugs could lead to the development of strategies for the general understanding of drug adverse reactions.

描述(改编自申请者摘要)：有不同的人类白细胞抗原 氯氮平引起的粒细胞缺乏症患者的相关性：IN 犹太患者，人类白细胞抗原B38，DR4(DRB1*0402，DQB1*0302，DQA1*0301，DPB1*0401)， HSP70 9.0-A，在非犹太患者中，人类白细胞抗原DR2(DRB1*1602，DQB1*0502， DQA1*0102)、HSP70 9.0-A、HLA-B44、DR7(DRB1*0701、DQB1*0202、DQB1*0201)、 HSP70 9.0-A。单倍型HLAB8，DR3(DRB1*0301，DQB1*0201，DQA1*0501， DPB1*0401)、HSP70 8.5-C和人类白细胞抗原B44、DR4(DRB1*0401、DQB1*0301、DQA1*0301)， HSP70 9.0-A与保护相关。初步研究表明 非人类白细胞抗原基因的常见变异(肿瘤坏死因子DNA星座；a，b，c，d，e 微卫星，TNFB的n内含子和TNFa启动子区域的-308) (按基因顺序b，a，n，c，-308，e，d) 组织相容性复合体(MHC)与人类白细胞抗原CA标志物相关。 此外，氯氮平及其代谢物也会增加细胞毒性。 或中性粒细胞的凋亡。阿司匹林诱导中性粒细胞死亡的实验研究 在纯合子的HLA-B8中，氯氮平及其代谢物显著减少， DR3、TNF-3、2、1、1、2、3、1(与CA耐药有关) 人类白细胞抗原B7、DR2、肿瘤坏死因子4 11、2、1、1、3、3、1或纯合子人类白细胞抗原-B38、DR4、肿瘤坏死因子 4、10、2、1、1、3、3个个体(与CA易感性相关)。 因此，非HLAMHC标记物可能是导致血液学并发症的基础。 精神分裂症患者的CA。该项目有以下具体内容 目标：1)对a)纯合子或 携带不同扩展单倍型的杂合子和b) 肿瘤坏死因子星座的纯合或杂合，可能是也可能不是 部分人类白细胞抗原扩展单倍型；2)犹太人和汉族尖锐湿疣患者的分型 肿瘤坏死因子DNA星座多态的非犹太血统特征 以确定不同民族CA的共同标志物；3) 在存在或不存在的情况下诱导中性粒细胞死亡 氯氮平及其代谢物在部分纯合子和杂合子中的分布 不同MHC单倍型的个体。肿瘤坏死因子基因多态性的研究 在药物存在的情况下与细胞生理的关系可能导致 制定全面了解药物不良反应的策略 反应。