TLR4 shapes BM HSCs and lymphopoiesis

TLR4 塑造 BM HSC 和淋巴细胞生成

基本信息

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
项目类别：
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

项目摘要

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.

抽象的骨髓造血茎和祖细胞（BM HSPC）表达先天免疫传感器细菌产物，包括Toll样受体4（TLR4）。出乎意料的是，我们最近在非 TLR4信号传导不足的小鼠的感染性环境在竞争性收养中胜过野生型转移。这些发现为基础TLR4信号在稳态中的作用开辟了新的调查途径造血。此外，这些观察结果提出了有关在标记的疾病状况下BM腐败的问题通过增加循环TLR4配体水平。在AIM 1中，我们将使用全基因组的方法来确定 TLR4缺陷型与足够的HSC的转录组和染色质结构，这是迈向的重要一步确定功能变化的分子基础。 AIM 2，我们将执行功能分离实验以区分两个不同的共受体CD14（LPS）与Fetuin的机理重要性 A（饱和脂肪），以肥胖症（一种全球负担的疾病）中依赖TLR4依赖性的HSPC淋巴样抑制。这这些研究的结果将大大提高我们对环境提示如何交付的理解通过标志性的先天免疫传感器形状BM造血过程。