Determining the conserved molecular mechanisms contributing to inflammation during Sepsis

确定脓毒症期间导致炎症的保守分子机制

基本信息

批准号：
10164718
负责人：
Susan Carpenter
金额：
$ 37.42万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-14 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10164718
关键词：
ATAC-seq Antisense RNA Bacteria Binding Biological Models Bone Marrow CRISPR/Cas technology Cause of Death Cells Centers for Disease Control and Prevention (U.S.)Chemicals Chimera organism Chromatin Clinical Clinical Treatment Clustered Regularly Interspaced Short Palindromic Repeats Complex Cytosol Data Endotoxic Shock Escherichia coli Future Gastric Adenocarcinoma Gene Expression Gene Expression Regulation Genes Genetic Genome Hospitals Human Human Genome Immune Immune response Infection Infiltration Inflammation Knock-out Knockout Mice Lead Length Mediating Molecular Mus Natural Immunity Nucleotides Pathway interactions Patients Phenotype Play Proteins RNA RNA Binding Regulation Resistance Role Sepsis Septic Shock Shock Small Interfering RNA Structure Testing Therapeutic Therapeutic Intervention Transcript Transgenes Transgenic Animals Transgenic Organisms Untranslated RNA design drug development in vivo insight knock-down knockout animal macrophage malignant stomach neoplasm monocyte mouse model neutrophil new therapeutic target overexpression progenitor response transcriptome sequencing

项目摘要

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.

项目摘要据估计，由于败血症，每年有超过600万人死亡。那里很少有患者的临床治疗选择，因此确定分子至关重要败血症期间发生的机制，以确定治疗干预的新目标。在这里，我们将长的非编码RNA（gaplinc）识别为人与人之间的保守基因在巨噬细胞中高度表达的小鼠。我们表明，大敲门量是抗性的唱片引起败血性休克。该提案的总体目的是确定如何张力导致导致败血性休克的免疫反应。在目标1中，我们将利用我们的遗传鼠标模型以扩展我们的初始发现，并确定什么影响敲除或 GAPLINC的过表达是对革兰氏阴性诱导的体内败血症的反应。在目标2中我们将确定GAPLINC使用的分子机制来影响免疫基因。我们将确定影响基因表达所需的最小区域。我们将确定复合物gaplinc用RNA或蛋白质发挥作用，最后我们将确定介导这些相互作用的GAPLINC中的任何结构特征。在目标3中我们将通过研究其在人类中的作用，确定gaplinc在人类中是否在功能上保守控制原代人单核细胞衍生巨噬细胞中的免疫基因。这个项目将使我们能够更好地了解细菌期间发挥作用的复杂机制诱发败血症。通过关注GAPLINC，我们将确定败血症期间的新调节层为我们提供未来药物开发的新途径。