PROJECT 1: VASCULAR AND CELLULAR PATHOLOGY IN DEPRESSION

项目 1：抑郁症中的血管和细胞病理学

• 批准号: 7959829
• 负责人: GRAZYNA RAJKOWSKA
• 金额: $ 22.78万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959829
• 关键词: Aftercare; Age; Animals; Antidepressive Agents; Autopsy; Blood Vessels; Brain-Derived Neurotrophic Factor; Cardiovascular Diseases; Cell Count; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Data; Depressive disorder; Down-Regulation; Electroconvulsive Shock; Fibroblast Growth Factor; Funding; Gene Expression; Genes; Grant; Growth Factor; Impairment; Individual; Institution; Lead; Link; Major Depressive Disorder; Microscopic; Molecular; Molecular Target; Monkeys; Morphology; Neuroglia; Neurons; Neurosciences; Pathology; Patients; Pharmaceutical Preparations; Prefrontal Cortex; Reporting; Research; Research Personnel; Resources; Risk Factors; Rodent; Source; Stress; United States National Institutes of Health; Vascular Diseases; brain tissue; cellular pathology; density; depressed; depression; design; inflammatory marker; neuroimaging; neurotrophic factor; novel; white matter

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. Depression and cardiovascular disease are often comorbid. Clinical studies report impairment of endothelial functions and increased inflammatory markers (risk factor for cardiovascular disease) in depressed patients. Moreover, structural neuroimaging studies demonstrate that depressed patients have more blood vessel pathology in the frontal white matter than age-matched non-depressed controls. However, no studies of vascular morphology and related growth factors at the microscopic and molecular level have been conducted in depression to date. Our preliminary data on microscopic analysis of vessel number and morphology in postmortem brain tissue reveal significant increases in the density of abnormal vessels in the prefrontal cortex (PFC) in depression. These vascular changes were observed in the same subjects that were used in our previous cell counting studies on reductions in the density of neurons and glial cells. Moreover, our recent gene expression studies in these depressed subjects reveal downregulation of genes for fibroblast growth factor (FGF) and brain-derived neurotrophic factor (BDNF), and rodent studies indicate that these factors are reduced in stressed animals and elevated after treatment with electroconvulsive shock or antidepressants. Thus, we hypothesize that in depression there are alterations in vascular morphology that are associated with deficits in angiogenic and neurotrophic factors as well as pathology of neurons and glial cells in the PFC. We further hypothesize that these changes are due to the depressive disorder itself and not due to treatment with antidepressant medication, therefore they will not be observed in the PFC of monkeys treated with antidepressants. This proposal will be the first quantitative microscopic study of cortical vasculature in major depression. It will likely reveal a link between dysfunctional genes and the expression of angiogenic and neurotrophic factors and the pathology of blood vessels, neurons and glial cells in the prefrontal cortex of depressed individuals. This may reveal novel cellular and molecular targets of antidepressant action and possibly lead to the design of more effective medications for depressed patients with vascular disease.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 抑郁症和心血管疾病通常合并。临床研究报告说，抑郁症患者的内皮功能损害和炎症标记（心血管疾病的危险因素）增加。此外，结构性神经影像学研究表明，抑郁症患者在额叶白质中比年龄匹配的非抑郁症对照更多的血管病理学更多。然而，迄今为止，在抑郁症中尚未对微观和分子水平的血管形态和相关生长因子进行研究。我们在验尸脑组织中有关血管数和形态的显微镜分析的初步数据显示，抑郁症前额叶皮质（PFC）中血管异常的密度显着增加。在我们以前的细胞计数研究中使用的有关神经元和神经胶质细胞密度降低的细胞计数研究中使用的同一受试者中观察到了这些血管变化。此外，我们最近在这些抑郁受试者中的基因表达研究表明，成纤维细胞生长因子（FGF）和脑衍生的神经营养因子（BDNF）的基因下调，啮齿动物研究表明，这些因素在压力动物中降低并在用电脱氧化处理后升高冲击或抗抑郁药。 因此，我们假设在抑郁症中，血管形态存在变化，与血管生成和神经营养因子缺陷以及PFC中神经元和神经胶质细胞的病理有关。我们进一步假设这些变化是由于抑郁症本身而不是由于用抗抑郁药治疗的，因此在用抗抑郁药处理的猴子的PFC中不会观察到它们。该建议将是严重抑郁症皮质脉管系统的首次定量微观研究。它可能会揭示功能失调基因与血管生成和神经营养因子的表达与抑郁个体前额叶皮质中血管，神经元和神经胶质细胞的病理学之间的联系。这可能揭示了抗抑郁作用的新型细胞和分子靶标，并可能导致为血管疾病抑郁症患者设计更有效的药物。