TLR4 shapes BM HSCs and lymphopoiesis

TLR4 塑造 BM HSC 和淋巴细胞生成

• 批准号: 9316026
• 负责人: Lisa Borghesi
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-06 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316026
• 关键词: ATAC-seq; Acute; Address; Adoptive Transfer; Area; Bacterial Infections; Biological; Biological Assay; Blood Cells; Bone Marrow; CD14 gene; Cells; Cellular biology; Chimera organism; Chromatin; Chromatin Structure; Chronic; Clinical; Colitis; Common Lymphoid Progenitor; Cues; Data; Dietary Fats; Disease; Dose; Environment; Exposure to; Genes; Genetic Transcription; Health; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; High Fat Diet; Immune; Infection; Inflammation; Investigation; Knock-out; Ligands; Link; Lipopolysaccharides; Lymphoid; Lymphoid Cell; Lymphopoiesis; Mediating; Messenger RNA; Modeling; Molecular; Mus; Myelogenous; Myelopoiesis; Obesity; Outcome Study; Pathway interactions; Process; Production; Publishing; Regulation; Reporting; Role; Saturated Fatty Acids; Serum; Shapes; Side; Signal Transduction; Stem cells; TLR4 gene; Technology; Testing; alpha-Fetoproteins; base; epigenetic profiling; exhaustion; experimental study; genome-wide; mouse model; nano-string; novel; progenitor; public health relevance; receptor; response; saturated fat; sensor; small molecule; transcriptome; transcriptome sequencing

Abstract Bone marrow hematopoietic stem and progenitor cells (BM HSPCs) express innate immune sensors for bacterial products including toll-like receptor 4 (TLR4). Unexpectedly, we recently demonstrated in a non- infectious setting that HSCs from TLR4 signaling deficient mice outcompete wild-type in competitive adoptive transfer. These findings open a new avenue of investigation into the role of basal TLR4 signals in steady-state hematopoiesis. Further, these observations raise questions about BM corruption in disease conditions marked by increased levels of circulating TLR4 ligands. In Aim 1, we will use genome-wide approaches to determine the transcriptome and chromatin structure of TLR4-deficient versus -sufficient HSCs, an essential step toward identifying the molecular basis of functional changes. Aim 2, we will perform separation-of-function experiments to distinguish the mechanistic importance of two distinct co-receptors, CD14 (LPS) versus Fetuin A (saturated fats), to TLR4-dependent HSPC lymphoid suppression in obesity, a disease of global burden. The outcomes of these studies will significantly advance our understanding of how environmental cues delivered through a hallmark innate immune sensor shape BM hematopoietic processes.

摘要 骨髓造血干细胞和祖细胞（BM HSPC）表达先天免疫传感器， 细菌产物，包括Toll样受体4（TLR 4）。出乎意料的是，我们最近在一个非- 来自TLR 4信号传导缺陷小鼠HSC在竞争性过继中胜过野生型的感染环境 转移这些发现为研究基础TLR 4信号在稳态中的作用开辟了新的途径 造血此外，这些观察结果提出了关于在疾病条件下BM腐败的问题， 通过增加循环TLR 4配体的水平。在目标1中，我们将使用全基因组方法来确定 TLR 4缺乏与足够的HSC的转录组和染色质结构，这是向 识别功能变化的分子基础。目标2，我们将执行分离功能 实验以区分两种不同的共受体，CD 14（LPS）与胎球蛋白的机制重要性 A（饱和脂肪），TLR 4依赖性HSPC淋巴抑制肥胖症，全球负担的疾病。的 这些研究的结果将大大推进我们对环境线索如何传递的理解， 通过标志性的先天免疫传感器塑造BM造血过程。