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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 各种死后大脑研究和临床调查提供了证据，证明被诊断患有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理解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，但仍不清楚什么特定的神经化学底物或机制负责重度抑郁症中5-羟色胺神经传递的缺陷。同样重要的是要注意到，全世界妇女的抑郁症发病率是男子的两倍，几项临床研究记录了治疗反应以及结构和功能脑成像测量的性别差异。 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，雌激素已被证明可以调节血清素的功能。虽然在了解抑郁症的病理生理学方面取得了进展，但仍然不知道是什么生物学机制使妇女容易患上抑郁症。该提议旨在检验以下假设：在被诊断患有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性的一种或多种关键神经元调节剂的生物合成中存在性别特异性改变，这产生5-羟色胺神经传递的缺陷。 这项拨款提案的具体目的是确定非常具体的降钙素相关分子的生物合成完整性，如血清素合成的限速酶，色氨酸羟化酶，5-HT 1A自身受体，降钙素相关转录因子和诊断为重度抑郁症的受试者特定脑区的重要传入神经调质。实验将在诊断为重度抑郁症的女性和男性受试者以及匹配的非精神病对照受试者的人类死后脑标本上进行。为了确定抑郁受试者的生化和细胞变化不是由抗抑郁药治疗的可能混杂影响引起的，将人死后生化测量值与在长期接受抗抑郁药治疗的非人雄性和雌性灵长类动物的相同脑区中进行的相同生化测量值进行比较。这些研究将利用几种组织学、生物化学和分子生物学程序，对含有中脑中缝背核和前额皮质的组织标本中各种多巴胺能分子的蛋白质和基因表达进行定量。了解生化机制有助于改变5-羟色胺生物合成和神经传递的抑郁症，特别强调性别的影响，将提供重要的信息，抑郁症的5-羟色胺系统的病理生理学，可能导致开发新的治疗策略，特别是在妇女抑郁症。