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: 8195990
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195990
• 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）： 项目摘要/摘要该提案是针对多站点研究的，该研究将在逻辑上扩展我们先前资助的Vamr-CSR＆D项目“代谢组学在精神病和治疗性监测中的应用”。我们的中心假设是，细胞膜磷脂异常代表了精神分裂症的病因学综合征中重要的生理亚型。更具体地说，我们建议涉及花生四烯酸和相关代谢产物（统称为eicosanoids）的异常是至少一种精神分裂症的生理亚型的基础。此外，我们提出，磷脂 - 氨基苯二甲酸盐（PAE）信号传导异常是烟酸降低性的原因（对烟酸皮肤冲洗作用的敏感性降低），这是选择性最广泛的生理异常之一。具体而言，拟议的工作将确定烟酸下敏性是精神分裂症亚型的稳定且可遗传的生理标志物，具有突出的PAE信号传导。最后，初步证据表明烟酸异常的反应是一种可遗传的特征，因此我们期望PAE信号传导异常将与受影响的探针的非精神病性一级亲戚（FDR）之间的烟酸下敏化的发生。为了研究这些问题，将从匹兹堡部位研究300例经临床稳定的临床稳定患者，100例双相情感障碍（BD）患者（BD）患者（BD）和100例人口统计学平衡的健康对照（HC）受试者。我们假设大约30％的CSZ患者将存在烟酸蛋白 - 屈服/PAE降低的内表型 - 在BD受试者或正常对照中将最少存在。我们预计烟酸的下敏性将与PAE信号通路中的缺陷相关，并且PAE成分与烟酸敏感性之间的预测关系可以数学上进行建模。 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,以及负责其的生化和/或遗传机制，在疾病的稳定阶段将持续存在。此外，我们将通过比较90名FDR和90个HC受试者（来自波特兰站点）来测试烟酸下敏性和血浆水平的遗传力。尽管实验证据仍处于发育的早期阶段，但大量的报告的报告支持烟酸下敏的有效性，作为精神分裂症的内型型。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，利用现有的VA支持基础设施（MIRECC）在匹兹堡站点招募CSZ和BD患者，并无需额外费用，在Portland现场招募CSZ和FDR患者，以招募CSZ和FDR患者。 公共卫生相关性： 项目叙事：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，以及是否可遗传异常。此外，这种膜异常可能导致对烟酸皮肤冲洗作用的敏感性降低。结果可能会导致改进的疾病早期检测方法，甚至可能是新类型的治疗方法。