Analysis of circadian profiles in cultured fibroblasts

培养的成纤维细胞的昼夜节律分析

• 批准号: 7268160
• 负责人: MAJA BUCAN
• 金额: $ 17.21万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-13 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268160
• 关键词: Activity Cycles; Affect; Affective; Bioluminescence; Biopsy; Bipolar Disorder; Bos taurus; Cattle; Cell Count; Cell Line; Cells; Characteristics; Chemicals; Circadian Rhythms; Clinical; Disease; Doctor of Philosophy; Endothelin; Exhibits; Fibroblasts; Forskolin; Functional disorder; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genome; Glucocorticoids; Human; Individual; Link; Lithium; Mental disorders; Methods; Monitor; Mood Disorders; Pathogenesis; Patients; Pattern; Phase; Polygenic Traits; Polymerase Chain Reaction; Purpose; Recurrence; Relative (related person); Rest; Risk; Serum; Shock; Skin; Sleep; Source; Symptoms; System; Time; age effect; base; circadian pacemaker; endophenotype; fetal; repository; sex

DESCRIPTION (provided by applicant): Some of the most prominent and characteristic symptoms of recurrent affective illnesses, e.g., bipolar and unipolar disorders, include dramatic disturbances in the sleep:wake or rest:activity cycle. It has been shown that manipulations of rest:activity cycles can profoundly change the course of clinical manifestations of these illnesses. These findings suggest that genetic predisposition to alterations in sleep:wake or rest:activity cycles represent endophenotypes for recurrent affective disorders. Based on recent findings that gene expression of 5-10% of genes in the genome are controlled by the clock (Akhtar et al., 2002; Panda et al., 2002), we propose that clock genes and/or genes that are controlled by the clock may underlie polygenic inheritance of the bipolar disorder. Recent findings that cultured skin fibroblasts, following a serum shock (50% fetal bovine serum) exhibit synchronized cycling in the expression of core clock genes (Balsalobre et al., 1998; Nagoshi et al., 2004) provide a new avenue to investigate the link between bipolar illness and the circadian system. The purpose of this application is to explore the possibility of using fibroblasts derived from skin biopsies of bipolar patients to investigate their intrinsic circadian clock. Specifically, our aims are: Aim 1. To develop a high-throughput method for monitoring circadian rhythms in human cultured fibroblasts to examine cycling expression of core clock and clock-controlled genes by Real-time quantitative PCR and bioluminescence recording; and Aim 2. To apply the method to examine if the core clock machinery is involved in the pathophysiology of bipolar disorder. In this aim will involve analysis of fibroblasts cell-lines available through the Coriell Cell Repositories (Important note: The identity of the specific individuals that were the source of the original cells is not known to the repository).This highly exploratory project has a tremendous potential for accelerating our understanding of the genetic basis of an important mental disorder.

描述（由申请人提供）：复发性情感疾病（例如双相情感障碍和单相情感障碍）的一些最突出和特征性症状包括睡眠：觉醒或休息：活动周期的剧烈紊乱。研究表明，控制休息：活动周期可以深刻改变这些疾病的临床表现的进程。这些发现表明，睡眠：觉醒或休息：活动周期改变的遗传倾向代表了复发性情感障碍的内表型。基于最近发现基因组中 5-10% 的基因表达受时钟控制（Akhtar 等，2002；Panda 等，2002），我们提出时钟基因和/或受时钟控制的基因生物钟可能是双相情感障碍多基因遗传的基础。最近发现，培养的皮肤成纤维细胞在血清休克（50% 胎牛血清）后表现出核心时钟基因表达的同步循环（Balsalobre 等人，1998；Nagoshi 等人，2004），这为研究双相情感障碍与昼夜节律系统之间的联系。本申请的目的是探索使用双相情感障碍患者皮肤活检来源的成纤维细胞来研究其内在生物钟的可能性。具体来说，我们的目标是： 目标 1. 开发一种高通量监测人类培养成纤维细胞昼夜节律的方法，通过实时定量 PCR 和生物发光记录检查核心时钟和时钟控制基因的循环表达；目标2.应用该方法检查核心时钟机制是否参与双相情感障碍的病理生理学。在此目标中，将涉及通过 Coriell 细胞存储库提供的成纤维细胞系的分析（重要提示：存储库不知道作为原始细胞来源的特定个体的身份）。这个高度探索性的项目具有巨大的意义加速我们对一种重要精神疾病遗传基础的理解的潜力。

项目成果

Genomic landscape of a three-generation pedigree segregating affective disorder.

• DOI: 10.1371/journal.pone.0004474
• 发表时间: 2009
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Yang, Shuzhang;Wang, Kai;Gregory, Brittany;Berrettini, Wade;Wang, Li-San;Hakonarson, Hakon;Bucan, Maja
• 通讯作者: Bucan, Maja