CELLULAR MECHANISMS OF DRUG REACTIONS IN SCHIZOPHRENIA

精神分裂症药物反应的细胞机制

• 批准号: 2033823
• 负责人: EDMOND J YUNIS
• 金额: $ 16.18万
• 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/2033823
• 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（改编自申请人摘要）：有不同的HLA 氯氮平诱导的粒细胞缺乏症（CA）患者的相关性： 犹太人患者，HLA-B38，DR 4（DRB 1 *0402，DQB 1 *0302，DQA 1 *0301，DPB 1 *0401）， HSP 70 9.0-A，而在非犹太人患者中，HLA-DR 2（DRB 1 *1602，DQB 1 *0502， DQA 1 *0102）、HSP 70 9.0-A、HLA-B44、DR7（DRB 1 *0701、DQB 1 *0202、DQB 1 *0201）、 HSP 70 9.0-A。 单倍型HLA-B8，DR 3（DRB 1 *0301，DQB 1 *0201，DQA 1 *0501， DPB1*0401）、HSP70 8.5-C和HLA-B44、DR 4（DRB1*0401、DQB 1 *0301、DQA 1 *0301）， HSP 70 9.0-A与保护有关。 初步研究表明 非HLA基因的常见变体（TNF DNA星座; a、B、c、d、e TNFB的内含子和TNFa的启动子区的-308） （以基因顺序B、a、n、c、-308、e、d给出） 组织相容性复合体（MHC）与HLA CA标志物相关。 氯氮平及其代谢产物也可增加细胞毒性 或嗜中性粒细胞的凋亡。 诱导中性粒细胞的细胞死亡 氯氮平及其代谢产物在纯合HLA-B8中显著较少， DR 3、TNF-3、2、1、1、2、3、1（与CA耐药相关） HLA-B7、DR 2、TNF-4 11、2、1、1、3、3、1或纯合子HLA-B38、DR 4、TNF 4、10、2、1、1、3、3个个体（与CA易感性相关）。 因此，非HLA MHC标记物可能是血液学并发症的基础。 精神分裂症患者的CA。 该项目具有以下具体 目的：1）分型非精神分裂症个体，其是a）纯合子或 携带不同扩展HLA单倍型的杂合的，和B） TNF星座的纯合或杂合， 部分HLA扩展单倍型; 2）犹太人和 非犹太血统，以表征TNF DNA星座多态性， 以确定不同民族CA的共同标志物; 3） 在存在或不存在以下物质的情况下诱导中性粒细胞的细胞死亡： 氯氮平及其代谢产物在选定的纯合子和杂合子 不同MHC单倍型的个体。 肿瘤坏死因子基因多态性在胃癌中的研究 在药物存在的情况下，与细胞生理学的关系可能导致 制定战略，以普遍了解药物不良反应 反应.