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: 8167932
• 负责人: GRAZYNA RAJKOWSKA
• 金额: $ 23.4万
• 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/8167932
• 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; Depressed mood; Depressive disorder; Down-Regulation; Electroconvulsive Shock; Fibroblast Growth Factor; Funding; Gene Expression; Genes; Grant; Growth Factor; Impairment; Individual; Institution; Lead; Link; Major Depressive Disorder; Mental Depression; Microscopic; Molecular; Molecular Target; Monkeys; Morphology; Neuroglia; Neurons; 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; 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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 抑郁症和心血管疾病通常是共存的。临床研究报告抑郁症患者的内皮功能受损和炎症标志物（心血管疾病的危险因素）增加。此外，结构神经影像学研究表明，抑郁症患者的额叶白质中比年龄匹配的非抑郁症患者有更多的血管病变。然而，迄今为止，尚未在抑郁症中进行血管形态和相关生长因子在微观和分子水平上的研究。我们对死后脑组织血管数量和形态进行显微分析的初步数据显示，抑郁症患者前额皮质（PFC）中异常血管的密度显着增加。这些血管变化是在我们之前针对神经元和神经胶质细胞密度减少的细胞计数研究中使用的同一受试者中观察到的。此外，我们最近在这些抑郁受试者中进行的基因表达研究揭示了成纤维细胞生长因子（FGF）和脑源性神经营养因子（BDNF）基因的下调，而啮齿动物研究表明，这些因子在应激动物中减少，在用电休克或抗抑郁药治疗后升高。 因此，我们假设在抑郁症中，血管形态发生改变，这与血管生成和神经营养因子以及前额皮层中神经元和神经胶质细胞的病理学缺陷有关。我们进一步假设这些变化是由抑郁症本身引起的，而不是由抗抑郁药物治疗引起的，因此在接受抗抑郁药物治疗的猴子的 PFC 中不会观察到这些变化。该提案将是第一个针对重度抑郁症皮质脉管系统的定量显微镜研究。它可能会揭示功能失调的基因与血管生成和神经营养因子的表达以及抑郁症个体前额皮质中血管、神经元和神经胶质细胞的病理学之间的联系。这可能揭示抗抑郁作用的新细胞和分子靶点，并可能导致为患有血管疾病的抑郁症患者设计更有效的药物。