Project 5-CREB and the other targets in Projects 1-4 in reward regions in depress

项目 5-CREB ​​和项目 1-4 中奖励地区的其他目标位于抑郁症地区

• 批准号: 8114145
• 负责人: Carol A Tamminga
• 金额: $ 19.21万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114145
• 关键词: Affect; Antidepressive Agents; Area; Autopsy; Biological Assay; Bipolar Depression; Brain; Brain-Derived Neurotrophic Factor; CREB1 gene; Chromatin; Circadian Rhythms; Collection; Complement; DNA; Depressed mood; Development; Diagnosis; Ensure; Feasibility Studies; Gene Expression Regulation; Gene Proteins; Genes; Genetic Risk; Genotype; Human; Hypothalamic structure; Major Depressive Disorder; Measures; Mental Depression; Mission; Modeling; Molecular; Molecular Target; Nucleus Accumbens; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Proteins; Rattus; Recording of previous events; Regulation; Research; Research Personnel; Rewards; Risk; Risk Factors; Rodent; Rodent Model; Sampling; Schizoaffective Disorders; Signaling Protein; Time; Tissues; Work; base; brain tissue; chromatin immunoprecipitation; chromatin remodeling; clinical phenotype; depressive symptoms; driving force; feeding; human subject; human tissue; insight; interest; molecular pathology; pre-clinical; pre-clinical research; receptor

Our Center has recently launched a new initiative to study CREB and the other molecular targets of interest to Projects 1-4 in brain reward regions of depressed humans on autopsy. This work focuses primarily on the NAc (nucleus accumbens) and VTA (ventraltegmental area). This endeavor represents a new Project 5 for the Center in this competitive renewal. We have already begun the collection of brains from depressed humans via the Dallas Brain Collection. Such collections have been proceeding at a rapid pace, which ensures the availability of an adequately large enough sample for meaningful analysis. The Project offers several powerful features for Center research. 1) We utilize the most stringent and rigorous measures of brain tissue quality, which is essential for postmortem brain studies. 2) Our focus on human brain reward regions complements most current efforts in the field, which have largely analyzed other brain circuits. 3) By focusing on the same genes and proteins that preclinical investigators study in rodent models of depression, the Project provides a major driving force for the critical translational mission of our Center. 4) We will examine these molecular targets both as a function of a diagnosis of depression (i.e., as seen in patients with major depression) and as a function of symptoms of depression (i.e., as seen across several diagnoses, including major depression, bipolar depression, and schizoaffective disorder with depression). 5) Alterations in molecular targets in the VTA and NAc will also be characterized as a function of developmental risk factors for depression (based on extensive history of the human subjects) and of particular genotypes recently implicated in genetic risk for depression. 6) The Project will study the possible influence of long-term antidepressant treatment on these molecular targets by treating rodents with prototypical agents for 6 months. We are very excited by the potential of this new initiative. We have demonstrated the feasibility of studying the various gene products of interest in human postmortem NAc and have already documented abnormalities in some of these products, which we know are altered in rodent depression models. At the same time, findings from the human tissue have provided new insight into regulation of these molecular pathways, which is guiding the preclinical research in the other Projects. Moreover, we have established the capability of carrying out advanced molecular analyses on human postmortem tissue, including, well beyond traditional DNA expression arrays, chromatin immunoprecipitation (ChIP), ChIP on chip, and microRNA assays in conjunction with the Chromatin and Gene Regulation Core. Together, the proposed studies will provide a uniquely powerful analysis of molecular pathologies in the human VTA-NAc associated with depression and its treatment.

我们中心最近启动了一项新计划来研究 CREB ​​和其他感兴趣的分子靶标 尸检中抑郁症患者大脑奖励区域中的项目 1-4。这项工作主要集中于 NAc（伏隔核）和 VTA（腹侧被盖区）。这项努力代表了一个新的项目 5 中心在这场竞争性的更新中。 我们已经开始通过达拉斯大脑收集中心收集抑郁症患者的大脑。 此类收集一直在快速进行，这确保了足够大的可用性 足够的样本进行有意义的分析。该项目为中心研究提供了多种强大的功能。 1） 我们采用最严格的脑组织质量测量方法，这对于尸检至关重要 大脑研究。 2）我们对人脑奖励区域的关注补充了该领域当前的大多数努力， 主要分析了其他大脑回路。 3）通过关注相同的基因和蛋白质 临床前研究人员在啮齿动物抑郁症模型中进行研究，该项目为 我们中心的重要转化使命。 4）我们将检查这些分子靶标的函数 抑郁症诊断的依据（即重度抑郁症患者所见）以及症状的函数 抑郁症（即，如多种诊断所示，包括重度抑郁症、双相抑郁症和 分裂情感性障碍伴抑郁症）。 5) VTA 和 NAc 中分子靶标的改变也将 被描述为抑郁症发育风险因素的函数（基于抑郁症的广泛历史） 人类受试者）以及最近与抑郁症遗传风险有关的特定基因型。 6) 项目 将通过治疗来研究长期抗抑郁治疗对这些分子靶点的可能影响 啮齿类动物使用原型药物治疗 6 个月。 我们对这项新举措的潜力感到非常兴奋。我们已经论证了研究的可行性 人类死后 NAc 中感兴趣的各种基因产物，并且已经记录在案 其中一些产品存在异常，我们知道这些异常在啮齿动物抑郁症模型中发生了改变。在 同时，来自人体组织的发现为这些分子的调节提供了新的见解。 途径，指导其他项目的临床前研究。此外，我们还建立了 对人类死后组织进行高级分子分析的能力，包括远远超出 传统 DNA 表达阵列、染色质免疫沉淀 (ChIP)、芯片上 ChIP 和 microRNA 与染色质和基因调控核心结合进行检测。总之，拟议的研究将 对人类 VTA-NAc 相关的分子病理学提供独特而强大的分析 抑郁症及其治疗。