Imaging organ system interfaces in ischemic heart disease

在这项应用中，我建议在检测和理解缺血性心脏病的先天免疫方面开展工作。 我将问一个最重要的问题，心血管疾病，更具体地说，是危险因素 高血压会影响骨髓中的造血，即先天免疫细胞的产生。我提议 解决两个主要目标：1.开发和验证基础科学和翻译成像工具，以 提供有关骨髓造血的体内数据，包括活体显微镜和正电子发射 断层扫描/磁共振成像；2.破译缺血性心脏病如何改变骨骼 骨髓功能，以及器官的炎性免疫细胞的输出。我现在的关注点是骨头 骨髓血管系统。这一焦点是由血管干细胞生态位的影响推动的，它指示 造血干细胞增殖、祖细胞偏向和白细胞迁移。同时， 骨髓血管是体循环的一部分，因此暴露在心血管风险和 促进疾病的途径。目前尚不清楚缺血心脏的骨髓血管系统是否以及如何发生变化 疾病，以及这些变化如何调节系统的先天免疫细胞供应。动机是有证据表明 全身性白细胞水平与心血管死亡率相关，我将与 最终目标是为动脉粥样硬化患者发现新的治疗靶点。

In this application, I propose to work on sensing and understanding innate immunity in ischemic heart disease. I will ask the overarching question how cardiovascular disease, and more specifically the risk factor hypertension, affects hematopoiesis, i.e. innate immune cell production, in the bone marrow. I propose to tackle two major goals: 1. to develop and validate fundamental science and translational imaging tools that provide in vivo data on bone marrow hematopoiesis, including intravital microscopy and positron emission tomography/magnetic resonance imaging; 2. to decipher how ischemic heart disease disease alters bone marrow function, and the organ's output of inflammatory immune cells. My immediate focus will be the bone marrow vasculature. This focus is motivated by the influence of the vascular stem cell niche, which instructs hematopoietic stem cell proliferation, progenitor lineage bias and leukocyte migration. At the same time, the bone marrow vasculature is part of the systemic circulation, and therefore exposed to cardiovascular risk and disease-promoting pathways. It is unknown if and how bone marrow vasculature changes in ischemic heart disease, and how these changes modulate systemic innate immune cell supply. Motivated by evidence that systemic leukocyte levels correlate with cardiovascular mortality, I will address this knowledge gap with the ultimate goal to discover new therapeutic targets for patients with atherosclerosis.