Lifestyle effects on hematopoiesis and atherosclerosis

 描述(申请人提供)：饮食、锻炼、压力和睡眠作为慢性炎症性疾病的重要环境调节剂受到关注。越来越多的证据表明，心理社会压力和高脂肪和高胆固醇的饮食会加剧病情，而定期的体育活动和健康的睡眠习惯有助于预防动脉粥样硬化。我们假设，临床上相关的环境输入会影响特定的生物免疫途径，这些途径可以作为逆转动脉粥样硬化疾病轨迹的靶点。造血是单核细胞及其后代巨噬细胞从多能祖细胞发育而来的过程，对疾病的发生和发展至关重要。造血对环境刺激进行调整，其结构与疾病的严重程度一致。随着动脉粥样硬化的恶化，对骨髓细胞产生的控制也会恶化。通过我们还不完全了解的机制，保护性的髓内壁龛驱逐造血祖细胞，造血祖细胞然后种植次级淋巴器官，在那里它们通过髓外造血产生炎症细胞。在疾病的晚期，即使是成熟的、完全分化的白细胞，也会在血管壁进行有限的造血。在这里，我们将检验一个假设，即现实生活中的疾病修饰物，如饮食、锻炼、压力和睡眠，会影响白细胞供应链。我们将使用小鼠模型测试，在动脉粥样硬化期间，生活方式如何改变造血的分子和细胞机制。我们认为“负性修饰”(高脂肪饮食、缺乏锻炼、慢性应激和睡眠不足)会重新安排造血地理位置，将生产从骨髓转移到外周，从而传播巨噬细胞供应链的数量和质量漂移。我们将研究控制巨噬细胞产生的微环境，包括调节造血的生长因子、细胞因子和黏附分子(祖细胞从骨髓到脾的增殖、保留和迁移模式)。APOE-/-和Ldlr-/-小鼠将暴露于各种生活方式的变化中，微环境因素将使用双基因敲除小鼠和依赖于纳米颗粒在体内启用的RNAi的功能基因组学方法进行研究。我们将进一步研究生活方式如何改变影响巨噬细胞及其前体细胞增殖、迁移和表型的细胞内在因素。具体地说，我们将针对导致髓系偏向的造血干细胞的转录因子。我们的动机是了解生活方式是如何改变造血的，以及这些转变是如何影响疾病进程的。随着公共卫生政策的改进，未来的疗法可能涉及将造血树推向逆转风险的方向。这项工作将极大地提高人们对白细胞在心血管疾病中是如何(过量)供应的理解。这些关于在暴露于现实生活中的危险因素后，造血系统是如何受到干扰的新见解，将为旨在减少 血管、心脏和大脑的炎症。

 DESCRIPTION (provided by applicant): Diet, exercise, stress and sleep are receiving attention as important environmental modifiers of chronic inflammatory diseases. Accumulating evidence indicates that psychosocial stress and a diet high in fat and cholesterol aggravate, whereas regular physical activity and healthy sleeping habits help to prevent atherosclerosis. We hypothesize that clinically relevant environmental inputs affect specific biological immune pathways that can be targeted to reverse the atherosclerosis disease trajectory. Hematopoiesis, the process by which monocytes and their descendant macrophages develop from multipotent progenitors, is essential to disease development and progression. Hematopoiesis adjusts to environmental stimuli, its configuration aligning with disease severity. As atherosclerosis worsens, control of cell production in the bone marrow deteriorates. Through mechanisms we do not fully understand, protective medullary niches expel hematopoietic progenitors, which then seed secondary lymphoid organs where they give rise to inflammatory cells through extramedullary hematopoiesis. At advanced stages of disease, even mature, fully-differentiated leukocytes undergo limited hematopoiesis in the vessel wall. Here, we will test the hypothesis that real-life modifiers of disease, such as diet, exercise, stress and sleep, influence the leukocyte supply chain. We will test, using mouse models, how lifestyle changes hematopoiesis' molecular and cellular machinery during atherosclerosis. We propose that "negative modification" (high fat diet, lack of exercise, chronic stress, and sleep deprivation) rearranges hematopoietic geography, diverting production from the bone marrow to the periphery, thus propagating a quantitative and qualitative drift of the macrophage supply chain. We will examine the microenvironment that governs macrophage production, including growth factors, cytokines and adhesion molecules that regulate hematopoiesis (proliferation, retention, migration patterns of progenitors from bone marrow to spleen). Apoe-/- and Ldlr-/- mice will be exposed to various lifestyle changes and microenvironmental factors will be studied using double knock out mice and functional genomics approaches which rely on nanoparticle-enabled in vivo RNAi. We will further study how lifestyle alters cell-intrinsic factors that influence proliferation, migraton and phenotype of macrophages and their progenitors. Specifically, we will target transcription factors which give rise to myeloid biased hematopoietic stem cells. Our motivation is to understand how lifestyle transforms hematopoiesis and how these transformations influence the course of disease. In conjunction with improvements in public health policy, future therapeutics may involve nudging the hematopoietic tree towards reversal of risk. The work will substantially improve understanding of how leukocytes are (over)supplied in the setting of cardiovascular disease. These new insights into how the hematopoietic system is perturbed after exposure to real-life risk factors will provide a foundation for new therapeutic strategies aiming at reduction of inflammation in blood vessels, in the heart and in the brain.