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

描述(申请人提供)：额颞叶痴呆是一种致命的神经退行性疾病，会导致行为、执行功能和语言的进行性下降。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多的了解，称为泛素化夹杂的额颞叶变性(FTLD-U)。2006年，FTLD-U标记的泛素化包涵体中的主要蛋白质被鉴定为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，有几条证据表明在基因表达的调控中起到了作用。TDP-43结合DNA和RNA，通过这些相互作用调节某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，生理上的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联系。这项研究方案是围绕这样一个假设而设计的，即通过TDP-43的异常活性，基因表达失调是FTLD-U的关键疾病机制。将使用全基因组方法来评估这一假说。该提案的具体目的如下：1.获得并分析FTLD-U在mRNA和microRNA水平上的全基因组表达谱。2.在细胞培养模型和FTLD-U中，利用TDP-43的染色质免疫沉淀和微阵列分析(ChlP-on-Chip)鉴定TDP-43的DNA结合伙伴。3.明确特定的microRNAs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其他以病理性TDP-43积聚为特征的疾病。相关性(见说明)：在65岁以下的人中，额颞部痴呆是第二大最常见的痴呆原因。了解这种疾病中调控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.