TLR4 shapes BM HSCs and lymphopoiesis

摘要 骨髓造血干细胞和祖细胞(BM HSPC)表达天然免疫感受器 细菌产物包括Toll样受体4(TLR4)。出乎意料的是，我们最近在一次非 TLR4信号缺陷小鼠HSCs竞争领养的感染性环境 调职。这些发现为研究基础TLR4信号在稳态中的作用开辟了一条新的途径 造血术。此外，这些观察结果提出了关于在标示的疾病条件下BM腐败的问题 通过增加循环中的TLR4配体水平。在目标1中，我们将使用全基因组方法来确定 TLR4缺乏与充足的HSCs的转录组和染色质结构，这是迈向 确定功能变化的分子基础。目标2，我们将执行职能分离 区分两种不同的辅受体CD14(脂多糖)和胎球蛋白的机制重要性的实验 A(饱和脂肪)，对TLR4依赖的HSPC淋巴抑制在肥胖这一全球性疾病中的负担。这个 这些研究的结果将极大地促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感应器塑造BM的造血过程。

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.