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

项目 3：分子

• 批准号: 8167934
• 负责人: MARK C AUSTIN
• 金额: $ 21.7万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167934
• 关键词: Anabolism; Antidepressive Agents; Applications Grants; Autopsy; Autoreceptors; Biochemical; Biological; Brain; Brain imaging; Brain region; Clinical; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Depressed mood; Depressive disorder; Diagnosis; Enzymes; Estrogens; Female; Functional disorder; Funding; Gender; Gene Expression; Grant; Human; Institution; Lead; Major Depressive Disorder; Measurement; Mental Depression; Midbrain structure; Molecular; Neuromodulator; Neurons; Ovarian hormone; Play; Prefrontal Cortex; Primates; Procedures; Proteins; Research; Research Personnel; Resources; Role; Serotonin; Source; Specimen; System; Testing; Tissues; Tryptophan 5-monooxygenase; United States National Institutes of Health; Woman; depressive symptoms; dorsal raphe nucleus; human male; male; men; neurochemistry; neurotransmission; 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 各种死后脑研究和临床研究提供的证据表明，被诊断为重度抑郁症的受试者大脑中的5-羟色胺神经传递减少。虽然临床和尸检研究为了解5-羟色胺在抑郁症的病理生理学中的作用提供了有价值的贡献，但目前尚不清楚是什么特定的神经化学底物或机制导致了重度抑郁症5-羟色胺神经传递的缺陷。还必须指出的是，全世界女性患抑郁症的比例是男性的两倍，几项临床研究记录了不同性别在治疗反应以及结构和功能脑成像测量方面的差异。 许多证据表明，卵巢激素在女性更容易患抑郁症方面发挥了作用，而雌激素已被证明可以调节血清素的功能。尽管在了解抑郁症的病理生理学方面取得了进展，但仍不清楚是什么生物学机制使女性容易患上抑郁症。这项建议旨在检验一种假设，即在诊断为重度抑郁症的女性受试者的中脑5-羟色胺神经元中，5-羟色胺合成或神经元活动的一个或多个关键神经调节因子的生物合成存在性别特异性的改变，从而导致5-羟色胺神经传递的缺陷。 这项拨款建议的具体目的是确定非常特定的5-羟色胺相关分子的生物合成完整性，例如5-羟色胺合成的限速酶、色氨酸羟基酶、5-HT1A自身受体、5-羟色胺相关的转录因子和重要的传入神经调节剂在诊断为重度抑郁症的患者的特定大脑区域中。这些实验将在人类死后大脑样本上进行，包括被诊断为严重抑郁症的女性和男性受试者，以及匹配的非精神控制组受试者。为了确定抑郁受试者的生化和细胞变化不是由抗抑郁药物治疗可能产生的混杂影响造成的，人类死后的生化测量将与在长期接受抗抑郁药物治疗的非人类雄性和雌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。这项研究将利用几种组织学、生化和分子生物学方法，对包含中脑中缝背核和前额叶皮质的组织标本中各种5-羟色胺能分子的蛋白质和基因表达进行量化。了解抑郁症中5-羟色胺生物合成和神经传递改变的生化机制，特别是性别影响，将为抑郁症中5-羟色胺系统的病理生理学提供重要信息，可能导致开发新的抑郁症治疗策略，特别是在女性中。