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.

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。 抑郁症和心血管疾病常常是共病的。临床研究报告了抑郁症患者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，抑郁症患者有更多的血管病变，在额叶白色问题比年龄匹配的非抑郁症的控制。然而，迄今为止，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。我们对死后脑组织中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层（PFC）中异常血管的密度显著增加。这些血管变化是在我们先前关于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相同受试者中观察到的。此外，我们最近在这些抑郁症患者中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，啮齿动物研究表明，这些因子在应激动物中减少，在电休克或抗抑郁药治疗后升高。 因此，我们假设，在抑郁症中有血管形态的改变，与血管生成和神经营养因子以及PFC中神经元和神经胶质细胞的病理缺陷相关。我们进一步假设，这些变化是由于抑郁症本身，而不是由于抗抑郁药物治疗，因此，它们不会在用抗抑郁药物治疗的猴PFC中观察到。这一建议将是第一次定量显微镜下研究皮层血管在重性抑郁症。它可能会揭示功能失调的基因和血管生成和神经营养因子的表达之间的联系，以及抑郁症患者前额叶皮层中血管，神经元和神经胶质细胞的病理学。这可能揭示新的抗抑郁作用的细胞和分子靶点，并可能导致设计更有效的药物治疗患有血管疾病的抑郁症患者。