Kynurenic Acid and Cognitive Abnormalities in Schizophrenia

犬尿酸与精神分裂症的认知异常

• 批准号: 9215693
• 负责人: ROBERT SCHWARCZ
• 金额: $ 214.44万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-09 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215693
• 关键词: Acute; Adult; Affect; Anabolism; Animal Model; Animals; Biological Markers; Brain; Cerebrospinal Fluid; Clinical; Clinical Investigator; Cognition; Cognitive; Cognitive deficits; Complex; Development; Diagnostic; Disease; Essential Amino Acids; Etiology; Functional disorder; Human; Immune; Immunization; Impaired cognition; Impairment; Individual; Inflammatory Response; Influentials; Institution; Instruction; Intervention; Kynurenic Acid; Kynurenine; Kynurenine-oxoglutarate aminotransferase; Laboratories; Link; Long-Term Effects; Mental disorders; Metabolism; N-Methyl-D-Aspartate Receptors; National Institute of Mental Health; Neuromodulator; Nicotine; Nursing Faculty; Pathology; Pathway interactions; Patients; Perinatal; Pharmaceutical Preparations; Pharmacology; Play; Population; Positioning Attribute; Pregnancy; Preparation; Process; Rattus; Research; Research Infrastructure; Risk Factors; Role; Schizophrenia; Science; Scientist; Series; Strategic Planning; Stress; Stressful Event; Symptoms; System; Testing; Therapeutic Intervention; Time; Tryptophan; Work; base; cognitive function; design; experience; inhibitor/antagonist; innovation; insight; neurodevelopment; new therapeutic target; novel; novel strategies; offspring; pre-clinical; programs

DESCRIPTION (provided by applicant): Several lines of evidence link the endogenous neuromodulator kynurenic acid (KYNA), a major metabolite of the essential amino acid tryptophan and antagonist of both a7 nicotinic and N-methyl-D-aspartate (NMDA) receptors, causally to the cognitive deficits seen in individuals with schizophrenia (SZ): 1) brain and cerebrospinal fluid KYNA levels are increased in SZ; 2) a7 nicotinic and NMDA receptors play critical roles in both neurodevelopment and cognition; 3) in animals, perinatal increases in brain KYNA cause an array of SZ-like abnormalities and vulnerabilities in adulthood; 4) experimental KYNA elevations cause cognitive dysfunctions reminiscent of SZ; 5) brain KYNA metabolism is stimulated by stress and immune stimulation during early development; and 6) first results indicate that inhibitors of KYNA biosynthesis ("KAT II inhibitors") show efficacy in animal preparations that are believed to be informative for SZ pathophysiology. The proposed Center is based on three premises: 1) SZ is a complex psychiatric illness in which stress/immune challenges during pregnancy set the stage for the emergence of the disease in vulnerable offspring; 2) Stressful events during development precipitate the early presentation of cognitive impairments in susceptible individuals by disproportionally elevating brain KYNA levels; and 3) Pharmacological reduction of brain KYNA synthesis offers a promising new therapeutic target in SZ, especially for pro-cognitive interventions. Hypotheses derived from these insights and from supportive preliminary results in animals and humans will be tested in two pre-clinical and two clinical projects. All studies will be led by established and highly interactive laboratory-based and clinical faculty, and the host institution has the appropriate infrastructure to embark on this overarching and highly synergistic translational project. Notably, the planned research strategy fits the Strategic Plan of the NIMH, which calls for a) discoveries of the causes of mental disorders, b) charting of disease trajectories to optimize treatment, and c) the development of new and better therapeutic interventions. RELEVANCE (See instructions): Deficits in cognitive functions are a core symptom of pathology in schizophrenia, a debilitating disorder affecting ~ 1 % of the world population. The proposed Center, organized in four highly complementary and synergistic projects in animals and humans, is designed to provide new insights into the role of the tryptophan metabolite kynurenic acid (KYNA) in cognition, and to examine inhibition of KYNA formation as a novel strategy to overcome cognitive impairments.

描述（由申请人提供）：多条证据表明内源性神经调节剂犬尿酸 (KYNA) 是必需氨基酸色氨酸的主要代谢物，也是 a7 烟碱和 N-甲基-D-天冬氨酸 (NMDA) 受体的拮抗剂，具有因果关系精神分裂症 (SZ) 患者的认知缺陷：1) 大脑和脑脊液中 KYNA 水平升高深圳； 2）a7烟碱受体和NMDA受体在神经发育和认知中发挥着关键作用； 3) 在动物中，围产期大脑 KYNA 的增加会导致成年期一系列类似 SZ 的异常和脆弱性； 4) 实验性 KYNA 升高导致认知功能障碍，让人想起 SZ； 5）大脑KYNA代谢在早期发育过程中受到应激和免疫刺激的刺激； 6) 第一个结果表明 KYNA 生物合成抑制剂（“KAT II 抑制剂”）在动物制剂中显示出功效，这被认为可以为 SZ 病理生理学提供信息。拟议的中心基于三个前提：1) SZ 是一种复杂的精神疾病，怀孕期间的压力/免疫挑战为易受影响的后代出现该疾病奠定了基础； 2) 发育过程中的压力事件通过不成比例地升高大脑 KYNA 水平，导致易感个体早期出现认知障碍； 3) 大脑 KYNA 合成的药理学减少为 SZ 提供了一个有前途的新治疗靶点，特别是对于促认知干预。从这些见解以及动物和人类的支持性初步结果中得出的假设将在两个临床前和两个临床项目中进行测试。所有研究都将由成熟且高度互动的实验室和临床教师领导，并且主办机构拥有适当的基础设施来开展这项研究 总体性且高度协同的转化项目。值得注意的是，计划中的研究策略符合 NIMH 的战略计划，该计划要求 a) 发现精神障碍的原因，b) 绘制疾病轨迹以优化治疗，以及 c) 开发新的、更好的治疗干预措施。相关性（参见说明）：认知功能缺陷是精神分裂症病理学的核心症状，精神分裂症是一种影响约 1% 世界人口的衰弱性疾病。拟议的中心由四个在动物和人类中高度互补和协同的项目组成，旨在为色氨酸代谢物犬尿酸（KYNA）在认知中的作用提供新的见解，并检查抑制 KYNA 形成作为一种新的策略克服认知障碍。