Spatial Control of Myeloid Differentiation

摘要： 越来越多的证据表明，血统决定是由支持分化的地方结构控制的 在骨髓的不同区域。我们操纵造血来治疗疾病的能力 因为我们对这些解剖学线索缺乏了解。 我们已经发现，HPC在BM中是区域性组织的，并且祖细胞和未成熟细胞属于 同一谱系分离到不同的血窦。我们还发现，有区域组织 CSF 1的产生，并且特定的BM血管是调节MDP、单核细胞和巨噬细胞的CSF 1的关键来源。 树突状细胞而不是HSC或巨噬细胞。中心假设是不同的血窦子集 作为装配线或枢纽，通过组织和维持不同的造血谱系， 谱系特异性细胞因子的产生。我们想了解这些细胞装配线是如何在 稳态和急性髓性白血病（AML）扰动后。 我们将从两个方面来检验这一假设。在目标1中，我们将确定这些装配线的生理学 使用原位克隆命运作图;鉴定每个装配线的组分;和条件性地删除 从每条装配线的关键部件中提取特定的细胞因子。在目标2中，我们将研究AML如何抑制 通过扰乱支持每条装配线的微环境来破坏正常的造血。

Abstract: Mounting evidence indicates that lineage decisions are controlled by local structures that support differentiation in distinct regions of the bone marrow. Our ability to manipulate hematopoiesis to treat disease has been hampered by our lack of understanding of these anatomical cues. We have found that HPC are regionally organized in the BM and that progenitors and immature cells belonging to the same lineage segregate to different sinusoids. We have also found that there is regional organization to CSF1 production and that specific BM vessels are critical sources of CSF1 that regulate MDP, monocytes and dendritic cells but not HSC or macrophages. The central hypothesis is that different subsets of sinusoids function as assembly lines or hubs that organize and maintain different hematopoietic lineages through the production of lineage-specific cytokines. We want to understand how these cellular assembly lines function in the steady-state and after perturbation by acute myeloid leukemia (AML). We will test this hypothesis in two aims. In Aim 1 we will determine the physiology of these assembly lines using clonal fate mapping in situ; identifying the components of each assembly line; and conditionally deleting specific cytokines from key components of each assembly line. In Aim 2 we will investigate how AML inhibits normal hematopoiesis by perturbing the microenvironment that supports each assembly line.