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: 9214790
• 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 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9214790
• 关键词: Acute leukemia; Agonist; Bone Marrow; CD34 gene; Cell Count; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Chronic; 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; Infection; 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; 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.

项目概要 该项目的目标是了解如何通过 Toll 样受体 2 (TLR2) 传递炎症信号 调节正常和癌前造血干细胞 (HSC)。 TLR2 是 TLR 家族的成员 在先天免疫反应中发挥核心作用的模式识别受体。对 TLR 的研究 主要集中于成熟的免疫细胞群，但 TLR 也在 HSC 上表达，最近的研究 报告表明，TLR 信号传导可能会影响 HSC 水平的免疫反应。 此外，TLR 信号传导失调，特别是 TLR2 表达和信号传导增加， 与骨髓增生异常综合征 (MDS) 相关，这是一组以无效为特征的 HSC 疾病 造血功能障碍，转化为急性白血病的风险很高。因此，异常的 TLR2 信号传导可能具有 对 HSC 具有临床显着的有害影响。 我们的初步数据表明 TLR2 信号影响 HSC 数量、动员和功能。 通过嵌合小鼠研究，我们确定 TLR2 信号传导对 HSC 的这些影响是由 细胞自主和细胞非自主机制。因此，我们假设 TLR2 信号传导 来自多种细胞类型的 TLR2 有助于 HSC 的调节，并且 TLR2 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 质谱流式细胞术和条件 敲除小鼠研究，以确定 TLR2 信号在 MDS 中增强的细胞类型，并确定 不同造血细胞和基质细胞类型的 TLR2 信号条件性丧失对 HSC 的监管。此外，我们将使用 MDS 小鼠模型，在其中我们可以增强或减少 TLR2 信号传导以检验增强的 TLR2 信号传导有助于该疾病发病机制的假设 疾病。这些研究将进一步加深我们对 TLR2 如何调节 HSC 的理解，并测试其作为调节剂的效用。 MDS 的治疗目标。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，我们预计这些研究不仅会对 MDS 的发病机制，但异常的 TLR 信号传导（例如慢性感染）可能如何导致其他疾病 骨髓衰竭和/或白血病发生的病例。未来的研究将建立在这些结果的基础上，并重点关注 TLR2 信号传导对 HSC 影响的下游介质，目的是识别 有助于响应 TLR 信号的 HSC 循环、分化、动员和/或功能丧失。