Phospholipid-Arachidonate-Eicosanoid Signaling in Schizophrenia

精神分裂症中的磷脂-花生四烯酸-类二十烷酸信号传导

• 批准号: 7796483
• 负责人: JEFFREY K YAO
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796483
• 关键词: Affect; Antipsychotic Agents; Arachidonic Acids; Award; Biochemical; Biological Markers; Bipolar Disorder; Blood flow; Catechols; Cell Membrane Structures; Cell membrane; Chemicals; Chronic Schizophrenia; Complex; Cutaneous; DSM-IV; Defect; Development; Diagnosis; Disease; Dose; Drug Interactions; Early Diagnosis; Eicosanoids; Energy Metabolism; Equilibrium; Etiology; Family; First Degree Relative; Flowmeters; Flushing; Functional disorder; Funding; Gene Expression; Genetic; Glutamates; Healthcare Systems; Heritability; Lasers; Lead; Light; Measures; Mediator of activation protein; Membrane; Membrane Structure and Function; Mental disorders; Metabolic; Methods; Modeling; Monitor; N-amyl-N-methylnitrosamine; Neurotransmitters; Nicotinic Acids; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phospholipids; Physiological; Plasma; Production; Psychotic Disorders; Publishing; Recruitment Activity; Reporting; Research; Research Infrastructure; Sampling; Schizoaffective Disorders; Schizophrenia; Series; Signal Pathway; Signal Transduction; Site; Skin; Staging; Study Subject; Symptoms; Syndrome; System; Testing; Therapeutic; Time; Vasodilator Agents; Visit; Work; abstracting; arachidonate; biological systems; chemical function; cost; cost effective; design; disability; endophenotype; improved; indoleamine; metabolomics; neurochemistry; novel; proband; public health relevance; receptor; research and development; response; theories; trait

DESCRIPTION (provided by applicant): Project Summary/Abstract This proposal is for a multi-site study that will logically extend the findings of our previously-funded VAMR- CSR&D project "Application of Metabolomics in Psychosis and Therapeutic Monitoring". Our central hypothesis is that abnormalities in cell membrane phospholipids represent an important physiological subtype within the etiologically complex syndrome of the schizophrenias. More specifically, we propose that abnormalities involving arachidonic acid and related metabolites (collectively termed eicosanoids) are fundamental to at least one physiological subtype of schizophrenia. Further, we propose that phospholipid-arachidonate-eicosanoid (PAE) signaling abnormalities are responsible for niacin subsensitivity (the reduced sensitivity to the skin flush effect of niacin), which is among the most widely-replicated physiological abnormalities selectively associated with schizophrenia. Specifically, the proposed work will determine the extent to which niacin subsensitivity is a stable and heritable physiological marker of a schizophrenia subtype featuring prominently disordered PAE signaling. Finally, preliminary evidence suggests abnormal niacin response to be a heritable trait, thus we expect that PAE signaling abnormalities will parallel the occurrence of niacin subsensitivity among non- psychotic first-degree relatives (FDR) of affected probands. To examine these questions, 300 neuroleptic- treated clinically stable patients with chronic schizophrenia (CSz), 100 patients with bipolar disorder (BD), and 100 demographically-balanced healthy control (HC) subjects will be studied from the Pittsburgh site. We hypothesize that the niacin-subsensitivity/PAE-disordered endophenotype will be present in approximately 30% of CSz patients - and will be minimally present among BD subjects or normal controls. We expect that niacin subsensitivity will be correlated with defects in PAE signaling pathways, and that a predictive relationship between PAE components and niacin sensitivity can be modeled mathematically. Using within- subjects and repeated-measures design to compare chemical mediators (plasma eicosanoid vasodilators, arachidonic acid and phospholipids) and the niacin flush EC50 values (the 1-methylnicotinate concentration required to elicit a half-maximal flush response) in 90 CSz patients (baseline and 6-month return visit from Portland site), we will demonstrate that niacin subsensitivity, as well as the biochemical and/or genetic mechanisms responsible for it, will persist during the stable phase of the illness. Moreover, we will test the heritability of niacin subsensitivity and plasma levels of eicosanoid vasodilators by comparing 90 FDR and 90 HC subjects (from Portland site). Although experimental evidence is still in its early stages of development, the preponderance of published reports supports the validity of niacin subsensitivity as a schizophrenia endophenotype. The proposed study will better characterize the metabolic and biochemical underpinnings of this novel biomarker. In addition, this is a cost-effective study utilizing existing VA-supported infrastructure (MIRECC) to recruit CSz and BD patients in Pittsburgh site, and VA-funded research development award (Dr. Messamore) to recruit CSz and FDR patients in Portland site at no additional costs. PUBLIC HEALTH RELEVANCE: Project Narrative: Schizophrenia is a leading cause of disability, but its causes are poorly understood. This project will determine whether certain cell membrane components (phospholipids, arachidonic acid, or eicosanoids) are affected in schizophrenia, and if the abnormalities are heritable. Furthermore, such membrane abnormalities may be responsible for reduced sensitivity to the skin flush effect of niacin. The results could lead to improved methods for early detection of the illness, and possibly, new types of treatment.

描述（由申请人提供）： 项目概要/摘要本提案是一项多中心研究，将合理地扩展我们以前资助的VAMR-CSR &D项目“代谢组学在精神病和治疗监测中的应用”的发现。我们的中心假设是，细胞膜磷脂的异常代表了精神分裂症的病因复杂综合征内的一个重要的生理亚型。更具体地说，我们提出，花生四烯酸和相关代谢物（统称为类花生酸）的异常是精神分裂症的至少一种生理亚型的基础。此外，我们提出，磷脂-花生四烯酸-类花生酸（PAE）信号传导异常负责烟酸亚敏感性（降低敏感性的皮肤潮红效应的烟酸），这是最广泛复制的生理异常选择性与精神分裂症。具体来说，拟议的工作将确定烟酸亚敏感性在多大程度上是一个稳定的和遗传的生理标志物的精神分裂症亚型具有显着紊乱的PAE信号。最后，初步证据表明，烟酸反应异常是一种遗传性状，因此我们预计PAE信号传导异常将与受影响先证者的非精神病一级亲属（FDR）中烟酸不敏感性的发生平行。为了检查这些问题，将对匹兹堡研究中心的300例经抗精神病药治疗的临床稳定的慢性精神分裂症（CSz）患者、100例双相情感障碍（BD）患者和100例人口统计学平衡的健康对照（HC）受试者进行研究。我们假设，烟酸亚敏感性/PAE紊乱的内表型将存在于约30%的CSz患者中，并且将在BD受试者或正常对照中最低限度地存在。我们预计，烟酸亚敏感性将与PAE信号通路中的缺陷相关，并且PAE组分和烟酸敏感性之间的预测关系可以在数学上建模。采用受试者内设计和重复测量设计比较化学介质（血浆类花生酸血管扩张剂、花生四烯酸和磷脂）和烟酸冲洗EC 50值（引起半数最大潮红反应所需的1-甲基烟酸酯浓度）（基线和波特兰研究中心的6个月回访），我们将证明烟酸亚敏感性，以及生物化学和/或遗传机制，将持续在疾病的稳定期。此外，我们将通过比较90例FDR和90例HC受试者（来自波特兰研究中心）来检测烟酸亚敏感性和类花生酸血管扩张剂血浆水平的遗传性。虽然实验证据仍处于发展的早期阶段，但已发表的大量报告支持烟酸亚敏感性作为精神分裂症内表型的有效性。拟议的研究将更好地表征这种新型生物标志物的代谢和生化基础。此外，这是一项具有成本效益的研究，利用现有VA支持的基础设施（MIRECC）在匹兹堡研究中心招募CSz和BD患者，并利用VA资助的研发奖（Messamore博士）在波特兰研究中心招募CSz和FDR患者，无需额外费用。 公共卫生关系： 项目叙述：精神分裂症是残疾的主要原因，但其原因知之甚少。该项目将确定某些细胞膜成分（磷脂、花生四烯酸或类花生酸）是否在精神分裂症中受到影响，以及这些异常是否是可遗传的。此外，这种膜异常可能导致对烟酸皮肤潮红效应的敏感性降低。研究结果可能会导致早期发现疾病的改进方法，并可能导致新的治疗方法。