DEPRESSION--PSYCHOPATHOLOGY BEYOND THE RECEPTORS

描述（改编自申请人的摘要）：抑郁症是一种常见的，但 复杂性疾病 先前的研究表明，损伤可能存在于 中枢β肾上腺素受体相关机制。 研究者打算 研究去甲肾上腺素能β受体以外的过程， 调解这些损伤。 在一项初步研究中，他评估了 12例原发性肝癌患者β肾上腺素受体连接cAMP依赖性PKA的活性 MDD和10名正常对照在皮肤获得的培养成纤维细胞样品中 活检 选择成纤维细胞是因为它们是容易获得的干细胞。 显示β-肾上腺素受体信号转导级联的细胞， 项目的兴趣。 数据表明，MDD患者 显著降低基础和cAMP刺激的PKA活性。 此外，本发明还 PKA介导的磷酸化活性降低， β肾上腺素受体信号转导级联反应的目的， 项目 数据表明，MDD患者的死亡率大大降低， 基础和cAMP刺激的PKA活性。 此外， β肾上腺素受体刺激PKA介导的磷酸化活性 激动剂ISO。 他建议在更大的样本中证实这些发现， 抑郁症和控制。 具体而言，此应用程序的目标是 1.招募并仔细诊断一组50人， DSM-IV MDD（COPD亚型）（SCID-P和SADS-L）和50例正常人 对照; 2）获得皮肤活检用于成纤维细胞培养; 3）评估 MDD组与正常对照组在基础和 cAMP刺激的PKA活性（通过PKA的磷酸化测定） PKA底物Kemptide）;和4）评估任何PKA底物的功能意义。 PKA异常通过测量PKA活性的激活， 肾上腺素能受体激动剂ISO和对照MDD和对照组。 这 该项目将确定MDD患者是否在 PKA水平的β肾上腺素受体-第二信使转导级联反应。

DESCRIPTION (Adapted from applicant's abstract): Depression is a common but complex disorder. Prior research suggests that impairments may exist in central beta adrenoceptor-linked mechanisms. The investigator intends to investigate processes beyond the noradrenergic beta receptor that may mediate these impairments. In a preliminary study, he has evaluated the activity of beta adrenoceptor-linked cAMP-dependent PKA in 12 persons with MDD and 10 normal controls in cultured fibroblast samples obtained by skin biopsy. Fibroblasts were chosen because they are readily available stem cells that display the beta-adrenoceptor signal transduction cascade of interest to the project. The data indicate that persons with MDD have substantially reduced basal and cAMP-stimulated PKA activity. Further, there is a reduction in PKA-mediated phosphorylation activity stimulated by the beta adrenoceptor signal transduction cascade of interest to the project. The data indicate that persons with MDD have substantially reduced basal and cAMP-stimulated PKA activity. Further, there is a reduction in PKA-mediated phosphorylation activity stimulated by the beta adrenoceptor agonist ISO. He proposes to confirm these findings in a larger sample of depressives and controls. Specifically, the goals of this application are to: 1) Recruit and very carefully diagnose a group of 50 persons with DSM-IV MDD (melancholic subtype) (by SCID-P and SADS-L) and 50 normal controls; 2) Obtain skin biopsies for fibroblast cell culture; 3) Evaluate differences between MDD and normal control groups in basal and cAMP-stimulated activity of PKA (as measured by the phosphorylation of the PKA substrate Kemptide); and 4) Assess the functional significance of any abnormalities in PKA by measuring the activation of PKA activity by the beta adrenoceptor agonist ISO and contrasting MDD and control groups. This project will determine whether persons with MDD display impairments in the beta adrenoceptor-second messenger transduction cascade at the level of PKA.