HUMAN PERINATAL INTERVENTION

人类围产期干预

• 批准号: 8120336
• 负责人: ROBERT R FREEDMAN
• 金额: $ 26.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120336
• 关键词: Adult; Age-Months; Agonist; Attention; Auditory; Auditory Evoked Potentials; Authorization documentation; Basic Science; Birth; Brain; Child; Choline; Chronic; Chronic Disease; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Cognitive; DBA/2 Mouse; Development; Double-Blind Method; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genotype; Glutamates; Goals; Human; Impaired cognition; Infant; Infant Development; Instruction; Intervention; Investigation; Lecithin; Life; Measures; Methods; Molecular; Mothers; NRG1 gene; Neuregulins; Neurobiology; Newborn Infant; Nicotine; Nicotinic Receptors; Nutrient; Outcome Measure; Parents; Perinatal; Pharmaceutical Preparations; Physiological; Pregnancy; Pregnant Women; Primary Prevention; Psychophysiology; Psychotic Disorders; Recording of previous events; Research; Research Support; Risk; Role; Schizophrenia; Smoke; Smooth Pursuit; Supplementation; Symptoms; Synapses; Techniques; Testing; Translating; base; design; follow-up; gamma-Aminobutyric Acid; genetic association; high risk infant; improved; mouse model; neuropsychological; new therapeutic target; novel therapeutics; offspring; perinatal intervention; prevent; primary outcome; randomized placebo controlled trial; receptor; research study; sensory gating

Primary prevention is a goal for the investigation of any chronic illness. Project 2 focuses on translating basic neurobiological findings about the role of alpha 7 nicotinic receptors in early brain development into clinical assessments of early human developmental abnormalities that can progress to schizophrenia later in life. It is also conducting initial tests of a specific perinatal intervention to reduce this risk. We have systematically examined the development of psychophysiological and neuropsychological abnormalities associated with the genetic liability to schizophrenia in adults. These include auditory sensory gating deficits demonstrated with PSO auditory evoked potentials, abnormalities in smooth pursuit eye movements, mismatch negativity, and various measures of attention. Abnormalities in these measures appear in some children of parents with schizophrenia as soon as testing is developmentally possible. Basic science research points to the perinatal period as a critical window for the role of alpha 7 nicotinic receptors, with their maximal expression occurring then as the adult forms of GABA and glutamate synapses are expressed. We developed techniques to record PSO sensory gating within several weeks of birth and showed that this function is already normally present. In the proposed aims, we will extend our initial observation that parental history of psychosis is associated with diminished PSO auditory sensory gating. Project 3 will genotype our subjects to test whether the genetic associations of these deficits in early development are the same as the associations in adults. Similar genetic association may support the hypothesis that the deficits in children at risk for schizophrenia have the same molecular basis as deficits observed in schizophrenia itself. We will also extend a second observation that maternal nicotine use during pregnancy is associated with diminished PSO auditory sensory gating. These effects are additive with the effects of apparent genetic risk and implicate nicotinic receptors in the deficit, as is also true in adults with schizophrenia who respond to chronic nicotine exposure with loss of PSO gating. Based on Project 3's demonstration that perinatal choline, an alpha 7 nicotinic receptor agonist, improves sensory gating in the DBA/2 mouse model of genetic deficiencies in alpha 7 nicotinic receptors and sensory gating, we have obtained FDA permission to administer perinatal choline to mothers and their infants. We will continue this clinical investigation, which shows initial promise of early enhancement of sensory gating. Project 2 receives clinical research support from Project 1 and basic research support from Projects 3,4,5,6. RELEVANCE (See instructions): New therapeutic strategies for schizophrenia are needed to improve cognitive dysfunction and negative symptoms and to prevent the development of psychosis. The Center investigates a nicotinic acetylcholine receptor as a new therapeutic target. Investigational results are used to design a new drug treatment for schizophrenia and a preventative nutrient intervention during infant development, both of which activate this rprpntnr

初级预防是任何慢性病调查的目标。项目2的重点是翻译 关于α7尼古丁受体在早期脑发育中作用的基本神经生物学研究 对早期人类发育异常的临床评估，这些异常可能在以后发展为精神分裂症 生活。它还在对特定的围产期干预措施进行初步测试，以降低这一风险。 我们系统地研究了心理生理学和神经心理学的发展。 与成人精神分裂症遗传易感性相关的异常。这些包括听觉感官 PSO听觉诱发电位显示门控缺陷，平滑追踪眼异常 运动，不匹配的消极情绪，以及各种注意力测量。这些措施中的异常情况 一旦检测有可能，就会出现在精神分裂症父母的一些孩子身上。 基础科学研究指出，围产期是阿尔法7尼古丁作用的关键窗口 受体，其最大表达发生在成体形式的GABA和谷氨酸突触 都被表达出来。我们开发了在出生后几周内记录PSO感觉门控的技术 显示此功能已正常存在。在拟议的目标中，我们将延长最初的 观察到父母的精神病病史与PSO听觉感觉门控的减少有关。 项目3将对我们的受试者进行基因分型，以测试这些缺陷的遗传关联是否在早期 发育与成人的联想是一样的。类似的基因关联可能支持 假设精神分裂症高危儿童的缺陷与缺陷具有相同的分子基础 在精神分裂症本身就能观察到。我们还将扩展第二个观察结果，即孕妇在服用尼古丁期间 妊娠与PSO听觉感觉门控减少有关。这些效果与 明显的遗传风险和牵连的尼古丁受体在缺陷中的影响，在患有糖尿病的成年人中也是如此 对长期尼古丁暴露有反应并失去PSO门控的精神分裂症患者。基于《项目3》的S 证明围产期胆碱，一种α7尼古丁受体激动剂，改善感觉门控在 DBA/2小鼠α7烟碱受体和感觉门控遗传缺陷的模型，我们有 获得了FDA的许可，可以给母亲及其婴儿服用围产期胆碱。我们将继续这样做 临床研究表明，早期加强感觉门控是有希望的。 项目2从项目1获得临床研究支持，从项目3、4、5、6获得基础研究支持。 相关性(请参阅说明)： 精神分裂症需要新的治疗策略来改善认知功能障碍和负性 并能预防精神病的发展。该中心研究一种烟碱型乙酰胆碱 受体作为新的治疗靶点。研究结果被用来设计一种新的药物治疗方法 精神分裂症和婴儿发育期间的预防性营养干预，两者都激活了这一 Rprpnnr