Dynamic Usage of Network Motifs in Retinal Development and Diseases

描述(由申请人提供)：视网膜发育通过各种调节机制受到严格控制，如转录调节、选择性剪接和microRNAs。视网膜调节网络的紊乱可导致各种视网膜疾病。高通量技术(例如，微阵列或下一代测序)已经确定了许多可能在视网膜基因调控中发挥作用的基因。然而，这些基因通常是单独识别的，没有提供关于它们之间相互作用的信息。以前的研究表明，分子回路很可能执行生物功能并定义视网膜的发育。识别调控网络中的关键分子回路有助于了解视网膜疾病的分子基础。本申请的目的是确定定义视网膜发育的网络基序(即分子回路)，以及它们在视网膜疾病中是如何受到干扰的。网络基序将由转录因子和microRNAs组成，它们是基因调控网络中两种重要的调节因子。提出这项研究的理由是。一旦我们确定了视网膜调控网络中的网络基序，我们就能够更好地了解视网膜疾病的分子机制，最终产生新的创新疗法来预防和治疗各种视网膜疾病。此外，这项研究将使我们能够从总体上了解转录因子和microRNAs之间的串扰。我们有两个特别的目标：1)鉴定调节视网膜发育和稳态的分子回路；2)鉴定调节视网膜退化和疾病的分子回路。在这项研究中，我们将整合几个大规模的数据集，包括染色质免疫沉淀结合微阵列(CHIP-CHIP)和测序(CHIP-SEQ)以及不同条件下的基因表达谱。然后，我们将确定正常和疾病视网膜调节网络中的网络基序。我们的方法是创新的，因为通过整合与视网膜调节相关的正交数据集，我们将能够从这些海量数据集中获得最大和关键的信息。这项拟议的研究具有重要意义，因为这是系统地识别各种视网膜条件下的网络主题的第一次努力。它还将把视网膜调节的范式从基于单个因素的分析转变为基于分子电路的分析。我们希望这些结果最终将促进我们对视网膜疾病机制的理解和新疗法的发展。

DESCRIPTION (provided by applicant): Retinal development is tightly controlled through a variety of regulatory mechanisms such as transcriptional regulation, alternative splicing, and microRNAs. Perturbation of the retinal regulatory network can lead to various retinal diseases. High-throughput technologies (e.g., microarray or next generation sequencing) have identified many genes that are likely to play a role in retinal gene regulation. However, these genes were often identified individually and no information was provided about their interactions between each other. Previous studies have suggested that it is likely that molecular circuits carry out biological functions and define the retinal development. Identification of the key molecular circuits in the regulatory network can help to understand the molecular basis of retinal diseases. The objectives of the present application are to identify network motifs (i.e., molecular circuits) that define the retinal development and how they are perturbed in retinal diseases. The network motifs will consist of transcription factors and microRNAs, two types of important regulators in gene regulatory network. The rationale for the proposed research is that. once we have determined the network motifs in retinal regulatory network, we will be able to better understand the molecular mechanisms of retinal disease, ultimately resulting in new and innovative therapeutics for the prevention and treatment of a variety of retinal diseases. In addition, this study will allow us to understand the crosstalk between transcription factors and microRNAs in general. We have two specific aims: 1) Identification of molecular circuits that regulate retinal development and homeostasis; and 2) Identification of molecular circuits that regulate retinal degeneration and diseases. For this study, we will integrate several large-scale datasets, including chromatin immunoprecipitation coupled with microarray (ChIP-chip) and with sequencing (ChIP-seq) and gene expression profiling in different conditions. We will then identify the network motifs in both normal and diseased retinal regulatory network. Our approach is innovative because by integrating orthogonal datasets relating to retinal regulation, we will be able to gain the maximal and key information from these massive datasets. This proposed research is significant because it is the first effort to systematically identify network motifs in various retinal conditions. It will also shift the paradigm from individual factor-based to molecular circuit-based analysis of retinal regulation. We expect the results will ultimately advance our understanding of retinal disease mechanisms and the development of novel therapeutics.