Dynamic Usage of Network Motifs in Retinal Development and Diseases

描述（由申请人提供）：视网膜发育通过多种调控机制（如转录调控、选择性剪接和microRNA）受到严格控制。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）已经鉴定了许多可能在视网膜基因调节中起作用的基因。然而，这些基因往往是单独确定的，没有提供关于它们之间相互作用的信息。以前的研究表明，分子电路可能执行生物功能并定义视网膜发育。识别调控网络中的关键分子回路有助于理解视网膜疾病的分子基础。本申请的目的是识别网络基元（即，分子电路），其定义视网膜发育以及它们在视网膜疾病中如何受到干扰。转录因子和microRNA是基因调控网络中两类重要的调控因子，它们构成了基因调控网络的模体。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，我们将能够更好地了解视网膜疾病的分子机制，最终产生预防和治疗各种视网膜疾病的新的和创新的疗法。此外，这项研究将使我们能够了解转录因子和microRNA之间的串扰。我们有两个具体目标：1）鉴定调节视网膜发育和稳态的分子回路;和2）鉴定调节视网膜变性和疾病的分子回路。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与微阵列（ChIP-chip）和测序（ChIP-seq）以及不同条件下的基因表达谱。然后，我们将确定在正常和患病的视网膜调控网络的网络图案。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。这项研究意义重大，因为它是首次系统地识别各种视网膜条件下的网络基序。它还将把视网膜调节的模式从基于个体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开发。 公共卫生相关性：识别视网膜发育和疾病中的关键分子回路可以提供对视网膜功能和疾病的分子基础的见解。这些分子回路可能是治疗视网膜疾病的潜在治疗靶点。

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. PUBLIC HEALTH RELEVANCE: Identification of key molecular circuits in retinal development and diseases can provide insights into the molecular basis of retinal function and diseases. These molecular circuits can be potential therapeutic targets for treatment of retinal diseases.