Impact of Infection and Inflammation on Primitive Hematopoiesis

项目摘要/摘要 骨髓中的造血干细胞(HSCs)负责调节大约10 每天十亿个血细胞。炎症在HSC功能中起关键作用，促进HSC分泌增加 应激或感染条件下的免疫细胞。然而，金博士之前的研究表明，长期的 在慢性分枝杆菌感染期间暴露于干扰素伽玛可改变HSC的自我更新和 分化，最终导致HSC耗尽和全血细胞减少。这一发现引发了一场爆炸 炎症与原始造血的关系及炎症作用的研究 在骨髓衰竭综合征、血液系统恶性肿瘤和与年龄相关的免疫功能减退。尽管 它与疾病的相关性，基本的问题仍然是关于炎症释放的机制 HSCs从静止状态和促进分化，以及血液学和免疫学后果 这些变化。拟议的研究方案建立在PI富有成效的研究记录的基础上，以 描述炎症调节原始生物的分子、转录和表观遗传机制 造血术。金博士已经确定了炎症诱导HSC分化的关键分子介质 包括转录因子BATF2和细胞表面粘附素Bst2，强调了这两个细胞如何内在地 细胞间相互作用中的转录变化和细胞外源性变化导致HSC活性改变 在发炎时。此外，金博士还推断了这项工作，以表明表观遗传学中的突变是如何 DNMT3A修饰剂削弱炎症诱导的HSCs分化，从而促进克隆性 造血是一种普遍的现象，与心脏病、中风和增加的死亡率有关。 老年人。在这项开创性工作的基础上，拟议的研究计划分为三个项目。 第一个项目将描述BATF2和BST2在炎症介导的HSC中的作用机制 差异化。这些机制研究将提供潜在的治疗靶点，以保存HSC的功能 慢性炎症的环境。第二个项目将量化HSC分化对克隆的影响 竞争，以提供对感染和炎症的关键洞察力，作为环境贡献者 克隆性造血，这是白血病和心血管疾病的危险因素。最后，第三个项目 将确定炎症诱导的HSCs转录和表观遗传学变化对 豁免权。这些研究将阐明肝星状细胞的炎症调节如何有助于形成和 免疫效应细胞的功能。总体而言，拟议的研究计划定义了 肝星状细胞上的炎性细胞因子信号，它们的寿命，以及它们维持健康血液和 免疫系统随着时间的推移。这些研究的长期目标是提供生理学知识 导致新的策略来保护和增强骨髓衰竭患者的骨髓功能， 癌症、干细胞移植和慢性炎症性疾病，以及广大老龄化人口。

Project Summary/Abstract Hematopoietic stem cells (HSCs) in the bone marrow are responsible for the regulated production of about ten billion blood cells per day. Inflammation plays a key role in HSC function, promoting increased production of immune cells during conditions of stress or infection. However, Dr. King’s prior work has shown that prolonged exposure to interferon gamma, induced during chronic mycobacterial infections, alters HSC self-renewal and differentiation, ultimately leading to HSC depletion and pancytopenia. This discovery spawned an explosion in research into the connections between inflammation and primitive hematopoiesis and the role of inflammation in bone marrow failure syndromes, hematologic malignancies, and age-associated impaired immunity. Despite its disease relevance, fundamental questions remain about the mechanisms by which inflammation releases HSCs from quiescence and promotes differentiation, and the hematologic and immunologic consequences of these changes. The proposed research program builds upon the PI’s productive research track record to delineate the molecular, transcriptional, and epigenetic mechanisms by which inflammation regulates primitive hematopoiesis. Dr. King has identified key molecular mediators of inflammation-induced HSC differentiation including the transcription factor Batf2 and the cell surface adhesin Bst2, highlighting how both cell intrinsic transcriptional changes and cell extrinsic alterations in cell-cell interactions contribute to altered HSC activity upon inflammation. Furthermore, Dr. King has extrapolated this work to show how a mutation in the epigenetic modifier Dnmt3a impairs inflammation-induced differentiation of HSCs and thereby contributes to clonal hematopoiesis, a widespread phenomenon linked to heart disease, stroke, and increased mortality in the elderly. Building on this groundbreaking work, the proposed research program is divided into three projects. The first project will delineate the mechanism of action of Batf2 and Bst2 in inflammation-mediated HSC differentiation. These mechanistic studies will provide potential therapeutic targets to preserve HSC function in the setting of chronic inflammation. The second project will quantify the impact of HSC differentiation on clonal competition in order to provide critical insight into infection and inflammation as an environmental contributor to clonal hematopoiesis, which is a risk factor for leukemia and cardiovascular disease. Finally, the third project will ascertain the importance of inflammation-induced transcription and epigenetic changes in HSCs to immunity. These studies will elucidate how inflammatory regulation of HSCs contributes to formation and function of immune effector cells. Collectively, the proposed research program defines the impact of inflammatory cytokine signaling on HSCs, their longevity, and their ability to maintain a healthy blood and immune system over time. The long-term goal of these studies is to provide physiologic knowledge that will lead to new strategies to protect and enhance bone marrow function for patients with bone marrow failure, cancer, stem cell transplant, and chronic inflammatory conditions, as well as for the aging population at large.