ROLE OF TLR2 IN REGULATING NORMAL AND PREMALIGNANT HEMATOPOIETIC STEM CELLS

TLR2 在调节正常和癌前造血干细胞中的作用

• 批准号: 9402647
• 负责人: LAURA G. SCHUETTPELZ
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9402647
• 关键词: Acute leukemia; Agonist; Bone Marrow; CD34 gene; Cell Count; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Cytometry; Data; Disease; Dysmyelopoietic Syndromes; Family; Future; Genes; Goals; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Human; Immune; Immune response; Individual; Ineffective Hematopoiesis; Inflammatory; Innate Immune Response; Knockout Mice; Ligands; Mediating; Mediator of activation protein; Mesenchymal; Mus; Myelogenous; NUP98 gene; Natural Immunity; Pancytopenia; Pathogenesis; Patients; Pattern recognition receptor; Play; Population; Premalignant; RNA; Regulation; Reporting; Research; Role; Signal Transduction; Source; Stromal Cells; TLR2 gene; Testing; Variant; cell type; chronic infection; clinically significant; cytopenia; high risk; leukemogenesis; loss of function; member; mouse model; pathogen; receptor; response; self-renewal; therapeutic target

PROJECT SUMMARY The goal of this project is to understand how inflammatory signaling through toll like receptor 2 (TLR2) regulates both normal and premalignant hematopoietic stem cells (HSCs). TLR2 is a member of the TLR family of pattern-recognition receptors that play a central role in the innate immune response. Studies of TLRs have largely focused on mature immune cell populations, however TLRs are also expressed on HSCs, and recent reports demonstrate that TLR signaling may influence the immune response from the level of the HSC. Furthermore, deregulated TLR signaling, and in particular increased TLR2 expression and signaling, is associated with myelodysplastic syndromes (MDS), a group of HSC disorders characterized by ineffective hematopoiesis and a high risk of transformation to acute leukemia. Thus, aberrant TLR2 signaling may have clinically significant detrimental effects on HSCs. Our preliminary data suggest that TLR2 signals influence HSC numbers, mobilization and function. Using chimeric mouse studies, we determined that these effects of TLR2 signaling on HSCs are mediated by both cell autonomous and cell non-autonomous mechanisms. We therefore hypothesize that TLR2 signaling from multiple cell types contributes to the regulation of HSCs, and TLR2-induced changes in HSC function may contribute to the pathogenesis of MDS. In this proposal we will use CyTOF mass cytometry and conditional knockout mouse studies to identify the cell types in which TLR2 signaling is enhanced in MDS and determine the effects of conditional loss of TLR2 signaling from different hematopoietic and stromal cells types to the regulation of HSCs. In addition, we will use a mouse model of MDS in which we either augment or reduce TLR2 signaling to test the hypothesis that enhanced TLR2 signaling contributes to the pathogenesis of this disease. These studies will further our understanding of how TLR2 regulates HSCs and test it's utility as a therapeutic target in MDS. More broadly, we hope to gain a better understanding of how TLR signals regulate both normal and premalignant HSCs, and we anticipate that these studies will have implications not only for the pathogenesis of MDS, but for how aberrant TLR signaling (e.g., chronic infection) may contribute to other cases of bone marrow failure and/or leukemogenesis. Future studies will build upon these results and focus on the downstream mediators of the effects of TLR2 signaling on HSCs, with the goal of identifying genes that contribute to HSC cycling, differentiation, mobilization and/or loss of function in response to TLR signals.

项目摘要 该项目的目标是了解炎症信号如何通过Toll样受体2（TLR 2） 调节正常和癌前造血干细胞（HSC）。TLR 2是TLR家族的一员 在先天免疫反应中起核心作用的模式识别受体。TLR的研究已经 主要集中在成熟的免疫细胞群体，然而TLR也在HSC上表达，并且最近 报告表明TLR信号可能从HSC水平影响免疫反应。 此外，TLR信号传导失调，特别是TLR 2表达和信号传导增加， 与骨髓增生异常综合征（MDS）相关，MDS是一组HSC疾病，其特征是无效的 造血和转化为急性白血病的高风险。因此，异常的TLR 2信号传导可能具有 对造血干细胞的临床显著有害作用。 我们的初步数据表明，TLR 2信号影响HSC的数量，动员和功能。 使用嵌合小鼠研究，我们确定TLR 2信号传导对HSC的这些作用是由 小区自主和小区非自主机制。因此，我们假设TLR 2信号传导 来自多种细胞类型的细胞参与HSC的调节，TLR 2诱导的HSC功能变化可能 有助于MDS的发病机制。在本提案中，我们将使用CyTOF质谱细胞术和条件 基因敲除小鼠研究，以鉴定MDS中TLR 2信号传导增强的细胞类型，并确定 不同造血细胞和基质细胞类型的TLR 2信号传导的条件性缺失对造血干细胞的影响。 调控HSC。此外，我们将使用MDS小鼠模型，其中我们增加或减少 TLR 2信号传导以测试增强的TLR 2信号传导有助于这种疾病的发病机制的假设。 疾病这些研究将进一步加深我们对TLR 2如何调节HSC的理解，并测试其作为一种免疫调节剂的效用。 MDS的治疗靶点。更广泛地说，我们希望更好地了解TLR信号如何调节 正常和癌前HSC，我们预计这些研究将不仅对 MDS的发病机制，但是异常TLR信号传导（例如，慢性感染）可能会导致其他 例骨髓衰竭和/或白血病。未来的研究将建立在这些结果的基础上，并侧重于 TLR 2信号传导对HSC作用的下游介质，目的是鉴定 在一些实施方案中，所述细胞因子促进HSC循环、分化、动员和/或响应TLR信号的功能丧失。