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

描述（由申请人提供）：重度抑郁症（MDD）是一种病因和表型复杂的疾病，可导致显著的发病率和死亡率。MDD通常与HIV感染共病，据报道，与一般人群相比，MDD在这一人群中的比例过高。我们的总体假设是，有一个生物学基础的基因表达，分子和细胞病理学的基础上，这些条件的共同发生。为了支持这一主张，在有记录的MDD病史的HIV感染者中，与没有MDD的人相比，我们已经证明（见初步数据）生长抑素、成纤维细胞生长因子-2（FGF 2）和生长停滞和DNA损伤诱导β（GADD 45 B）的额叶皮质基因表达显著降低，血清/糖皮质激素调节激酶1（SGK 1）的基因表达增加。SGK 1受糖皮质激素和应激的调节，在神经退行性变期间在大脑中显著增加，促进树突生长，并参与学习和记忆。Gadd 45 B也是一种应激反应基因，受SGK 1和HIV的调控。我们已经通过定量实时聚合酶链反应（qRT-PCR）验证了生长抑素基因表达的缺失，这与钙结合蛋白免疫阳性中间神经元的密度相关，并且我们注意到在产生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）。我们在患有MDD的HIV感染个体中观察到FGF 2基因表达降低，最近在患有MDD的非感染个体中也观察到了这种现象{Evans，2004#782}，我们已经概括了暴露于皮质醇的人脑聚集体中FGF 2的降低（参见初步数据）。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（FGF 2，GADD 45 A/B和SGK 1）在人脑中的表达，这些基因来自死于HIV，MDD和合并风险的人，以及那些没有风险的人。通过这种方式，我们将确定HIV和MDD在基因表达水平上是否存在共性。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物中的时间表达。这些数据将为阐明HIV感染者MDD的潜在病理机制提供基础。

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.