PROJECT 1: VASCULAR AND CELLULAR PATHOLOGY IN DEPRESSION

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。 抑郁症和心血管疾病常常是并存的。临床研究报告了抑郁症患者的内皮功能受损和炎症标志物(心血管疾病的风险因素)增加。此外，结构神经成像研究表明，抑郁症患者额叶白质的血管病变比年龄匹配的非抑郁症对照组更多。然而，到目前为止，还没有在微观和分子水平上对抑郁症的血管形态和相关生长因子进行研究。我们对死后脑组织血管数量和形态的显微镜分析的初步数据显示，抑郁症患者前额叶皮质(PFC)异常血管密度显著增加。这些血管变化是在我们之前的细胞计数研究中观察到的，这些对象是关于神经元和神经胶质细胞密度减少的。此外，我们最近对这些抑郁受试者的基因表达研究显示，成纤维细胞生长因子(FGF)和脑源性神经营养因子(BDNF)的基因下调，而啮齿动物研究表明，这些因子在应激动物中减少，在电惊厥或抗抑郁药物治疗后升高。 因此，我们假设抑郁症患者存在血管形态的改变，这些改变与血管生成因子和神经营养因子的缺乏以及前额叶神经元和神经胶质细胞的病理改变有关。我们进一步假设，这些变化是由于抑郁障碍本身，而不是由于抗抑郁药物的治疗，因此它们不会在接受抗抑郁药物治疗的猴子的PFC中观察到。这项建议将是首次对重度抑郁症患者的皮质血管系统进行的定量显微研究。它可能会揭示功能障碍基因与血管生成和神经营养因子的表达以及抑郁症患者前额叶皮质血管、神经元和神经胶质细胞的病理之间的联系。这可能揭示抗抑郁作用的新的细胞和分子靶点，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。

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.