Somatostain & Stress-Related Genes in HIV & Comorbid Major Depressive Disorder

描述(由申请人提供)：重度抑郁障碍(MDD)是一种病因和表型复杂的疾病，会导致显著的发病率和死亡率。MDD通常与艾滋病毒感染共存，据报告，与普通人群相比，MDD在这一群体中的比例过高。我们最重要的假设是，基于基因表达、分子和细胞病理学，这些疾病的共同发生有生物学基础。为了支持这一命题，与没有MDD病史的人相比，我们已经证实(见初步数据)在有MDD病史的HIV感染者中，额叶皮质生长抑素、成纤维细胞生长因子-2(FGF2)和生长停滞和DNA损伤诱导的β(GADD45B)的基因表达显著降低，而血清/糖皮质激素调节的激酶1(SGK1)的基因表达增加。SGK1受糖皮质激素和应激的调节，在神经退行性变的过程中，它在大脑中显著增加，促进树突生长，并参与学习和记忆。Gadd45B也是一个受SGK1和HIV调控的应激反应基因。我们已经通过实时定量聚合酶链式反应(qRT-PCR)证实了生长抑素基因表达的缺失，这与Calbindin免疫阳性中间神经元的密度有关，我们注意到产生HIV调节nef蛋白的转基因小鼠MDDel中皮质生长抑素免疫阳性神经元的数量显著减少(见初步数据)。我们观察到患有MDD的HIV感染者的FGF2基因表达减少，最近在MDD的非感染者中观察到了(Evans，2004#782)，我们概述了暴露于皮质醇的人脑聚集中FGF2的减少(见初步数据)。这项建议的一个重要目标是量化我们的候选生长抑素和应激相关基因(FGF2、GADD45A/B和SGK1)在人脑中的表达，这些基因来自死于艾滋病毒、MDD和复合风险的人，以及那些既没有风险又没有风险的人。通过这种方式，我们将确定HIV和MDD之间是否在基因表达水平上存在共同点。我们还将评估这些候选基因在HIV动物模型中的表达，并研究这些基因在体外神经元培养中的时间表达。这些数据将为阐明HIV感染者MDD潜在的病理机制提供基础。

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is an etiologically and phenotypically complex disorder causing significant morbidity and mortality. MDD is often comorbid with HIV infection and is reported to be over-represented in this group compared to the general population. Our overarching hypothesis is that there is a biological basis for the co-occurrence of these conditions based on gene expression, molecular and cellular pathology. In support of this proposition, in HIV infected individuals with a documented history of MDD compared to those without MDD, we have demonstrated (see preliminary data) a significant decrease in the frontal cortical gene expression of somatostatin, fibroblast growth factor-2 (FGF2) and growth arrest and DNA-damage-inducible-beta (GADD45B), and an increase in gene expression of serum/glucocorticoid regulated kinase 1 (SGK1). SGK1 is regulated by glucocorticoids and stress, it is significantly increased in the brain during neurodegeneration, promotes dendritic growth and is involved in learning and memory. Gadd45B is also a stress response gene that is regulated by SGK1 and HIV. We have validated the loss of somatostatin gene expression by quantitative real-time polymerase chain reaction (qRT-PCR), which correlates with the density of calbindin immunopositive interneurons and we noted a significant decrease in the number of cortical somatostatin immunopositive neurons in a transgenic mouse MDDel producing the HIV regulatory nef protein (see preliminary data). Our observation of decreased FGF2 gene expression in HIV infected individuals with MDD has recently been observed in non-infected individuals with MDD {Evans, 2004 #782} and we have recapitulated the reduction in FGF2 in human brain aggregates exposed to cortisol (see preliminary data). An important goal of this proposal is to quantify our candidate somatostatin and stress-related gene expression (FGF2, GADD45A/B and SGK1) in human brain derived from persons who died with HIV, MDD and combined risks, as well as those who had neither risk. In this way we will establish whether commonalities exist between HIV and MDD at the gene expression level. We will also assess the expression of these candidate genes in HIV animal models and investigate the temporal expression of these genes in in vitro neuronal cultures. The data will provide a foundation for clarifying the underlying potential pathological mechanisms of MDD in HIV-infected individuals.