Lifestyle effects on hematopoiesis and atherosclerosis

 描述（由申请人提供）：饮食、运动、压力和睡眠作为慢性炎症性疾病的重要环境调节剂而受到关注。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，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，临床相关的环境输入影响特定的生物免疫途径，可以针对扭转动脉粥样硬化疾病的轨迹。造血是单核细胞及其后代巨噬细胞从多能祖细胞发育的过程，对疾病的发展和进展至关重要。造血调节环境刺激，其配置与疾病的严重程度。随着动脉粥样硬化的恶化，骨髓中细胞生成的控制也会恶化。通过我们不完全理解的机制，保护性髓龛排出造血祖细胞，然后播种次级淋巴器官，在那里它们通过髓外造血产生炎性细胞。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中进行有限的造血。在这里，我们将测试这一假设，即现实生活中的疾病调节剂，如饮食，运动，压力和睡眠，影响白细胞供应链。我们将使用小鼠模型测试生活方式如何改变动脉粥样硬化期间造血的分子和细胞机制。我们认为，“负面修改”（高脂肪饮食，缺乏运动，慢性压力，睡眠不足）重新安排造血地理，转移生产从骨髓到外周，从而传播的巨噬细胞供应链的定量和定性漂移。我们将研究控制巨噬细胞产生的微环境，包括生长因子，细胞因子和调节造血（增殖，保留，祖细胞从骨髓到脾脏的迁移模式）的粘附分子。Apoe-/-和Ldlr-/-小鼠将暴露于各种生活方式变化，并将使用双敲除小鼠和功能基因组学方法研究微环境因素，这些方法依赖于纳米颗粒激活的体内RNAi。我们将进一步研究生活方式如何改变影响巨噬细胞及其祖细胞增殖、迁移和表型的细胞内在因素。具体地说，我们将靶向转录因子，这些转录因子产生骨髓偏向造血干细胞。我们的动机是了解生活方式如何改变造血，以及这些转变如何影响疾病的进程。结合公共卫生政策的改善，未来的治疗方法可能涉及推动造血树逆转风险。这项工作将大大提高对心血管疾病中白细胞是如何（过度）供应的理解。这些关于造血系统在暴露于现实生活中的危险因素后如何受到干扰的新见解将为旨在减少造血干细胞损伤的新治疗策略提供基础。 血管、心脏和大脑中的炎症。

 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.