Determining the conserved molecular mechanisms contributing to inflammation during Sepsis

项目摘要 据估计，全世界每年有超过600万人死于败血症。那里 患者的临床治疗选择很少，因此，确定分子水平至关重要。 研究败血症期间发生的机制，以确定治疗干预的新靶点。 在这里，我们确定了长的非编码RNA，GAPLINC，作为一个保守的基因之间的人类和 在巨噬细胞中高度表达的小鼠。我们发现GAPLINC敲除具有耐药性， LPS诱导的感染性休克。该提案的总体目标是确定GAPLINC如何 导致感染性休克的免疫反应在目标1中，我们将利用 遗传小鼠模型，以扩大我们的初步发现，并确定什么影响敲除或 GAPLINC的过表达响应于体内革兰氏阴性诱导的脓毒症。在目标2中 我们将确定GAPLINC影响免疫基因的分子机制。 我们将确定影响基因表达所需的GAPLINC内的最小区域。我们将 确定GAPLINC与RNA或蛋白质形成的复合物的功能， 将识别GAPLINC中介导这些相互作用的任何结构特征。在目标3 我们将通过研究GAPLINC在人类中的作用， 控制原代人单核细胞衍生的巨噬细胞中的免疫基因。该项目将 使我们能够更好地了解在细菌生长过程中起作用的复杂机制， 诱发败血症。通过关注GAPLINC，我们将确定脓毒症过程中的一个新的调节层 为我们未来的药物开发提供了新的途径。

Project Summary Worldwide it is estimated that over 6 million people die each year as a result of sepsis. There are few clinical treatment options for patients, therefore, it is critical to determine the molecular mechanisms that occur during sepsis in order to identity new targets for therapeutic intervention. Here we identify the long noncoding RNA, GAPLINC, as a conserved gene between human and mice that is highly expressed in macrophages. We show that GAPLINC knockouts are resistant to LPS induced septic shock. The overall aim of this proposal is to determine how GAPLINC contributes to the immune response that leads to septic shock. In Aim 1 we will utilize our genetic mouse models to expand on our initial findings and determine what impact knockout or overexpression of GAPLINC has in response to gram negative induced sepsis in vivo. In Aim 2 we will determine the molecular mechanisms utilized by GAPLINC to influence immune genes. We will identify the minimal region within GAPLINC required to impact gene expression. We will determine the complexes GAPLINC makes either with RNA or proteins to function and finally we will identify any structural features within GAPLINC that mediates these interactions. In Aim 3 we will determine if GAPLINC is functionally conserved in humans by studying its role in controlling immune genes in primary human monocyte derived macrophages. This project will enable us to better understand the complex mechanisms that are at play during bacterial induced sepsis. By focusing on GAPLINC we will identify a new layer of regulation during sepsis providing us with new avenues for future drug development.