PROJECT 3: MOLECULAR & CELLULAR INTEGRITY OF THE SEROTONIN SYSTEM IN DEPRESSION

项目 3：分子

• 批准号: 8360508
• 负责人: MARK C AUSTIN
• 金额: $ 22.7万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360508
• 关键词: Anabolism; Antidepressive Agents; Applications Grants; Autopsy; Autoreceptors; Biochemical; Biological; Brain; Brain imaging; Brain region; Clinical; Clinical Research; Clinical Trials; Depressed mood; Depressive disorder; Diagnosis; Enzymes; Estrogens; Female; Functional disorder; Funding; Gender; Gene Expression; Grant; Human; Lead; Major Depressive Disorder; Measurement; Mental Depression; Midbrain structure; Molecular; National Center for Research Resources; Neuromodulator; Neurons; Neurosciences; Ovarian hormone; Play; Prefrontal Cortex; Primates; Principal Investigator; Procedures; Research; Research Infrastructure; Resources; Role; Serotonin; Source; Specimen; System; Testing; Tissues; Tryptophan 5-monooxygenase; United States National Institutes of Health; Woman; cost; depressive symptoms; dorsal raphe nucleus; male; men; neurochemistry; neurotransmission; protein expression; research study; transcription factor; treatment response; treatment strategy

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A variety of postmortem brain studies and clinical investigations have provided evidence that serotonin neurotransmission is reduced in the brain of subjects diagnosed with major depression. While the clinical and postmortem studies have provided a valuable contribution towards understanding the role of serotonin in the pathophysiology of depression, it remains unclear what specific neurochemical substrate or mechanism is responsible for the deficit in serotonin neurotransmission in major depression. It is also important to note that worldwide women have twice the rate of depression as that of men, and several clinical studies have documented gender-specific differences in treatment responses and in structural and functional brain imaging measurements. Many lines of evidence suggest that ovarian hormones play a role in women's greater vulnerability to depression, and estrogen has been shown to modulate serotonin function. Although progress is being made in understanding the pathophysiology of depression, it remains unknown what the biological mechanisms are that make women vulnerable to developing depressive disorders. This proposal is intended to test the hypothesis that there is a gender-specific alteration in the biosynthesis of one or more key neuronal regulators of serotonin synthesis or neuronal activity which produces a deficit in serotonin neurotransmission in midbrain serotonin neurons of female subjects diagnosed with major depression. The specific aims of this grant proposal are intended to determine the biosynthetic integrity of very specific serotonin-related molecules such as the rate-limiting enzyme for serotonin synthesis, tryptophan hydroxylase, 5-HT1A autoreceptors, serotonin-related transcription factors and important afferent neuromodulators in specific brain regions of subjects diagnosed with major depression. The experiments will be conducted on human postmortem brain specimens of both female and male subjects diagnosed with major depression and matched non-psychiatric control subjects. To determine that the biochemical and cellular changes in depressed subjects are not resulting from the possible confounding influence of antidepressant treatment, the human postmortem biochemical measurements will be compared to identical biochemical measurements conducted in the same brain regions of non-human male and female primates that have been chronically treated with an antidepressant. The studies will utilize several histological, biochemical and molecular biological procedures to quantify protein and gene expression of the various serotonergic molecules in tissue specimens containing the midbrain dorsal raphe nucleus and prefrontal cortex. Understanding the biochemical mechanisms contributing to the alterations in serotonin biosynthesis and neurotransmission in depression, with a special emphasis on gender influences, will provide important information regarding the pathophysiology of the serotonin system in depressive illness that may lead to developing new treatment strategies for depression, particularly in women.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 多种死后大脑研究和临床研究提供了证据，表明在诊断为严重抑郁症的受试者的大脑中，5-羟色胺神经传递降低。虽然临床和验尸研究为了解5-羟色胺在抑郁症的病理生理学中的作用提供了宝贵的贡献，但仍不清楚哪种特定的神经化学底物或机制是导致5-抑郁症中5-羟色胺神经传递的不足。同样重要的是要注意，全世界女性的抑郁率是男性的两倍，而几项临床研究已经证明了治疗反应以及结构和功能性脑成像测量的性别特异性差异。 许多证据表明，卵巢激素在女性更大的抑郁症中起作用，并且已证明雌激素可以调节5-羟色胺的功能。尽管在理解抑郁症的病理生理学方面正在取得进展，但尚不清楚哪种生物学机制使女性容易发生抑郁症。该提案旨在检验以下假设，即5-羟色胺合成或神经元活性的一个或多个关键神经元调节剂的生物合成发生了一种特异性改变，这会导致诊断为主要脑脑抑郁症的女性脑脑性抑郁症患者的5-羟色胺神经传递的不足。 The specific aims of this grant proposal are intended to determine the biosynthetic integrity of very specific serotonin-related molecules such as the rate-limiting enzyme for serotonin synthesis, tryptophan hydroxylase, 5-HT1A autoreceptors, serotonin-related transcription factors and important afferent neuromodulators in被诊断为严重抑郁症的受试者的特定大脑区域。该实验将对被诊断为严重抑郁症和匹配的非精神病对照受试者的男性和男性受试者的人类后脑标本进行。为了确定抑郁受试者的生化和细胞变化不是抗抑郁药治疗的混淆影响而产生的，将将人类验尸后的生化测量与在非人类男性和女性灵长类动物的相同大脑区域进行的相同的生化测量进行比较已长期用抗抑郁药治疗。这些研究将利用几种组织学，生化和分子生物学程序来量化含有中脑背侧核核和前额叶皮质的组织标本中各种血清素能分子的蛋白质和基因表达。了解促进抑郁症中5-羟色胺生物合成和神经传递改变的生化机制，并特别强调性别影响，将提供有关5-羟色胺系统的重要信息在女性中。