Regulation of gene expression in frontotemporal dementia: A genome-wide approach

描述（由申请人提供）：额颞叶痴呆是一种致命的神经退行性疾病，导致行为、执行功能和语言能力的进行性下降。目前还没有有效的治疗方法。然而，最近的进展使人们对这种疾病最常见的病理形式有了更深入的了解，这种疾病被称为泛素化包涵体（FTLD-U）的额颞叶变性。2006年，FTLD-U泛素化包体中的主要蛋白被鉴定为TAR DMA结合蛋白43 （TDP-43）。TDP-43的功能在很大程度上是未知的。然而，几条线索的证据表明，在基因表达调控的作用。TDP-43结合DNA和RNA，通过这些相互作用调节一些基因的时间和组织特异性表达，以及其他基因的剪接。此外，生理性的TDP-43是核的，它与具有众所周知的剪接活性的异质核糖核蛋白相关。本研究计划是围绕这样的假设设计的：通过TDP-43的异常活性，基因表达失调是FTLD-U的一个关键疾病机制。全基因组方法将被用来评估这一假设。以下是该提案的具体目标：获取并分析FTLD-U在mRNA和microRNA水平上的全基因组表达谱。2. 利用TDP-43的染色质免疫沉淀和芯片微阵列分析（ChlP-on-chip），在细胞培养模型和FTLD-U中鉴定TDP-43的DNA结合伙伴。3. 表征特异性microrna和TDP-43与mRNA表达变化的关系。4. 将FTLD-U研究中开发的技术推广到以病理性TDP-43积累为特征的其他疾病。相关性（见说明）：额颞叶痴呆是65岁以下人群中导致痴呆的第二大常见原因。了解这种疾病中失调的关键基因可能会导致靶向治疗的发展。

DESCRIPTION (provided by applicant): Frontotemporal dementia is a fatal neurodegenerative disease that results in progressive decline in behavior, executive function, and language. Currently, there are no effective treatments. Recent advances, however, have led to a greater understanding of the most common pathological form of the disease, called frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). In 2006, the major protein in the hallmark ubiquitinated inclusions of FTLD-U was identified as TAR DMA binding protein 43 (TDP-43). The function of TDP-43 is largely unknown. However, several lines of evidence indicate a role in the regulation of gene expression. TDP-43 binds DNA and RNA, regulating through these interactions the temporal and tissue-specific expression of some genes, as well as the splicing of others. Moreover, physiologic TDP-43 is nuclear, where it associates with heterogeneous ribonucleoproteins with well-known splicing activities. This research proposal is designed around the hypothesis that through aberrant activity of TDP-43, dysregulation of gene expression is a key disease mechanism in FTLD-U. Genome-wide approaches will be employed to evaluate this hypothesis. The following are the proposal's specific aims: 1. Obtain and analyze genome-wide expression profiles of FTLD-U at the mRNA and microRNA levels. 2. Identify DNA binding partners of TDP-43 in cell culture models and in FTLD-U using chromatin immunoprecipitation of TDP-43 followed by microarray analysis (ChlP-on-chip). 3. Characterize the relationship of specific microRNAs and TDP-43 to changes in mRNA expression. 4. Extend techniques developed in the study of FTLD-U to other diseases characterized by the accumulation of pathologic TDP-43. RELEVANCE (See instructions): Frontotemporal dementia is the second-most common cause of dementia in individuals under age 65. Understanding key genes dysregulated in this disease could lead to the development of targeted therapies.