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Trophic Factors in Cognition

认知中的营养因素

基本信息

批准号：
10685440
负责人：
Samuel Newton Sathyanesan
金额：
$ 37.38万
依托单位：
UNIVERSITY OF SOUTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-11 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685440
关键词：
Acute Adverse effects Anemia Anti-Inflammatory Agents Attention Behavior Behavioral Behavioral Assay Biochemical Biological Assay Bipolar Disorder Blood Vessels Blood Viscosity Blood coagulation Brain CREB1 gene Chemical Engineering Chronic Clinic Clinical Clinical Trials Cognition Cognitive Cognitive deficits Dangerousness Data Development Disease Dorsal Dose Erythropoietin Erythropoietin Receptor Event Functional disorder Goals Health Hematopoiesis Hematopoietic Hemostatic Agents Hippocampus Hormones Human Impaired cognition Impairment Individual Knockout Mice Knowledge Ligands Major Depressive Disorder Marketing Mediating Memory Mental Depression Mental disorders Molecular Molecular Mechanisms of Action Neurobiology Neurocognitive Neuronal Dysfunction Neuronal Plasticity Neurons Neurotransmitters Nuclear Pathway interactions Performance Peripheral Pharmaceutical Preparations Physiological Platelet Count measurement Play Property Psychiatry Receptor Signaling Red Blood Cell Count Regulation Resolution Risk Rodent Role Safety Schizophrenia Short-Term Memory Signal Transduction Stress Testing Therapeutic Therapeutic Agents Thinking Transgenic Mice Viral blood-brain barrier crossing clinical translation cognitive enhancement cognitive function dentate gyrus experimental study functional disability genetic manipulation hippocampal subregions improved insight nervous system disorder neurobiological mechanism neuropsychiatric disorder neurotrophic factor novel object recognition pharmacologic pre-clinical preservation receptor receptor function social stress therapeutic development transcription factor

项目摘要

The progress in understanding how neuronal dysfunction can lead to nervous system disorders has drawn attention to the central role played by trophic factors in modulating brain function. Cognitive deficits, which are widely prevalent in neuropsychiatric disorders, are known to be regulated by trophic factors. The hippocampal actions of neurotrophic factors have been shown to be particularly important, influencing cellular pathways and mechanisms to produce behavioral effects. Erythropoietin (EPO), a naturally occurring hormone and trophic factor, widely prescribed to treat anemia, exerts robust neurotrophic actions in the brain. Moreover, peripheral administration is sufficient to elicit CNS effects in several preclinical and clinical psychiatry studies. Multiple human studies have demonstrated that EPO produces cognitive enhancing effects. The regulation of behavior is considered to be a result of neurotrophic activity that is independent of EPO’s physiological and hemostatic role in regulating hematopoiesis. However, the specific trophic mechanisms in the brain have not been characterized. Furthermore, the use of an inherently erythropoietic molecule to produce therapeutic neurotrophic effects can lead to elevated blood viscosity and increase the risk for adverse vascular events. We therefore utilize chemically engineered EPO derivatives that are non-erythropoietic but retain neurotrophic activity, to investigate the role of its hippocampal actions in cognition. Employing a combination of conditional, region-specific, receptor knockout mice and viral-mediated gene manipulation we will determine the role of hippocampal neurotrophic factor-driven mechanisms at the molecular, cellular and behavioral levels. Our studies are expected to provide new insight into trophic factor-mediated modulation of cognitive behavior and also inform the development of novel trophic factor based therapeutic agents.

在了解神经元功能障碍如何导致神经系统疾病方面取得了进展，引起了人们对营养因子在调节脑功能中所起的中心作用的关注。认知缺陷，已知其受营养因子调节，在神经精神疾病中广泛存在。神经营养因子的海马作用已被证明是特别重要的，影响细胞途径和机制以产生行为效应。促红细胞生成素a 天然存在的激素和营养因子，广泛用于治疗贫血，神经营养作用。此外，外周给药足以引起CNS效应，几项临床前和临床精神病学研究。多项人体研究表明，EPO 产生认知增强效应。行为的规范被认为是神经营养活性是独立的EPO的生理和止血作用，调节造血然而，大脑中的特定营养机制尚未被表征。此外，使用固有的红细胞生成分子产生治疗性神经营养作用，可导致血液粘度升高并增加不良血管事件的风险。因此我们利用非红细胞生成但保留神经营养活性的化学工程EPO衍生物，来研究海马体在认知中的作用。使用条件组合，区域特异性，受体敲除小鼠和病毒介导的基因操作，我们将确定的作用海马神经营养因子驱动机制的分子，细胞和行为水平。我们的研究有望为营养因子介导的认知功能调节提供新的见解。行为，并告知新的营养因子为基础的治疗剂的发展。