Impact of Infection and Inflammation on Primitive Hematopoiesis

项目总结/摘要 骨髓中的造血干细胞（HSC）负责调节约10种造血干细胞的产生。 十亿个血细胞炎症在HSC功能中起着关键作用，促进HSC产生增加。 免疫细胞在压力或感染的情况下。然而，金博士先前的工作表明， 在慢性分枝杆菌感染期间，暴露于干扰素γ，改变了HSC的自我更新， 分化，最终导致HSC耗竭和全血细胞减少。这一发现引发了 研究炎症与原始造血的关系及炎症的作用 在骨髓衰竭综合征、血液恶性肿瘤和年龄相关免疫力受损中。尽管 尽管它与疾病相关，但关于炎症释放的机制的基本问题仍然存在， 造血干细胞从静止期和促进分化，以及血液学和免疫学的后果， 这些变化。拟议的研究计划建立在PI的生产性研究记录的基础上， 阐明炎症调节原始细胞的分子、转录和表观遗传机制， 造血金博士已经确定了炎症诱导的HSC分化的关键分子介质 包括转录因子Batf 2和细胞表面粘附素Bst 2，强调了细胞内在的 转录变化和细胞-细胞相互作用中的细胞外在改变有助于改变HSC活性 在炎症上。此外，金博士推断这项工作，以显示如何在表观遗传突变。 修饰剂Dnmt 3a损害炎症诱导的HSC分化，从而促进HSC的克隆形成。 造血，一种与心脏病，中风和死亡率增加有关的普遍现象， 老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Batf 2和Bst 2在炎症介导的HSC中的作用机制 分化这些机制的研究将提供潜在的治疗靶点，以保持HSC的功能， 慢性炎症的发生第二个项目将量化HSC分化对克隆形成的影响。 竞争，以提供关键的洞察感染和炎症作为一个环境因素， 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 将确定炎症诱导的转录和HSC表观遗传变化的重要性， 免疫力这些研究将阐明HSC的炎症调节如何促进HSC的形成， 免疫效应细胞的功能。总的来说，拟议的研究计划定义了 HSC上的炎性细胞因子信号传导，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， 为骨髓衰竭患者提供保护和增强骨髓功能新策略， 癌症、干细胞移植和慢性炎症，以及整个老龄化人口。

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.