Cellular and molecular mechanisms of HSC dysfunction in chronic inflammation

 描述(由申请人提供)：血细胞生产受损与发病率和死亡率有关。血细胞补充的经典模型正在发生变化，人们意外地意识到，长期造血干细胞(LT-HSCs)通过Toll样受体(Toll-like Receptor，TLR)直接感知病原体并对其做出反应。在TLR刺激后，LT-HSC增殖，并优先进行髓系特异性分化。对TLR配体的直接感应被认为使HSCs能够补充在感染期间迅速耗尽的先天免疫细胞。然而，与短期激活HSC的潜在好处相反，慢性TLR刺激显著损害了长期HSC的功能。我们最近发现，在体内长期暴露于小剂量TLR4激动剂的小鼠HSCs过度增殖，表现出髓系倾斜，并且无法自我更新。这些观察具有重要的意义，因为TLR4可以被慢性感染患者中存在的血浆脂多糖(LPS)激活，也可以被肥胖患者中长期升高的脂多糖和饮食脂质激活。然而，TLR4介导的HSC衰竭的细胞和分子机制在很大程度上仍不清楚。在目标1中，我们确定了炎性细胞因子的作用，以及TLR4感觉的细胞来源，在每一个确定的脂多糖介导的HSC偏斜的实验模型和肥胖的疾病模型中。在目标2中，我们研究了HSC偏斜的分子机制。这些研究将首次建立TLR刺激损害HSC功能的细胞和分子机制，并将开辟新的研究领域，以研究在健康和疾病中保持HSC完整性的机制。

 DESCRIPTION (provided by applicant): Impaired production of blood cells is associated with morbidity and mortality. The classical model for blood cell replenishment is changing with the unexpected realization that long-term hematopoietic stem cells (LT-HSCs) directly sense and respond to pathogens via toll-like receptors (TLRs). Following TLR stimulation, LT-HSCs proliferate and preferentially undergo myeloid-specific differentiation. Direct sensing of TLR ligand is thought to enable HSCs to replenish innate immune cells that are rapidly depleted during infection. However, in contrast to the potential benefits of short-term HSC activation, chronic TLR stimulation dramatically impairs long-term HSC function. We recently showed that murine HSCs chronically exposed to low-dose TLR4 agonist in vivo hyperproliferate, exhibit myeloid skewing, and fail to self-renew. These observations have important implications because TLR4 can be activated by plasma lipopolysaccharide (LPS) present in patients with chronic infection as well as by both LPS and dietary lipids that are chronically elevated in patients suffering from obesity. However, the cellular and molecular mechanisms underlying TLR4-mediated HSC exhaustion remain largely unknown. In Aim 1, we determine the role of inflammatory cytokines, and the cellular source of TLR4 sensing, in each a defined experimental model of chronic LPS-mediated HSC skewing and in the disease model of obesity. In Aim 2, we examine the molecular mechanisms underlying HSC skewing. These studies will be the first to establish the cellular and molecular mechanisms by which TLR stimulation impairs HSC function, and will open new areas of investigation into the mechanisms that preserve HSC integrity in health and disease.