Direct visualization and characterization of hypoxia in the bone marrow

描述(申请人提供)：造血是由造血干细胞(HSCs)形成血细胞的过程。成年造血干细胞存在于骨髓(BM)内一个特殊的微环境中，称为造血干细胞小生境，其解剖和功能特性才刚刚开始被发现。微环境的重要性从以下事实中得到了说明：从其利基中取出的HSCs尚未成功地在体外扩增。虽然多种细胞成分和可溶性因子被证明有助于HSC生态位的建立，但在考虑体内HSC的生物学时，氧作为调节细胞功能的关键生理因素的中心作用不能被忽视。BM通常被认为是低氧的(低氧分压)，但局部氧分布与HSC壁龛显微解剖之间的关系仍然不清楚，部分原因是我们无法以细胞分辨率探测体内的氧分压。在这里，我们建议开发分子成像技术，以实现高分辨率的3D可视化和定量的活体小鼠骨髓局部氧分压。我们将利用这项技术来研究HSC在骨髓中的归巢和滞留是否受局部氧分压和缺氧诱导因子-1(HIF-1)依赖的细胞反应的调节。我们将进一步研究无氧代谢是否对体内HSC的功能是必要的。拟议的研究需要一个多学科研究团队的密切合作，这些研究人员在分子成像、光学技术和干细胞生物学方面拥有不同的专业知识。 公共卫生相关性：叙述性造血是由驻留在骨髓中的造血干细胞形成血细胞的过程。我们建议研究干细胞如何对骨髓中的氧气分布做出反应。

DESCRIPTION (provided by applicant): Hematopoiesis is the process of blood cell formation from hematopoietic stem cells (HSCs). Adult HSCs reside in a special microenvironment within the bone marrow (BM) called the HSC niche whose anatomical and functional properties are just beginning to be uncovered. The importance of the microenvironment is illustrated by the fact that HSCs taken out of their niche have yet to be successfully expanded ex vivo. While multiple cellular components and soluble factors have been shown to contribute to the establishment of the HSC niche, the central role of oxygen as a critical physiological factor governing cell function cannot be overlooked in considering the biology of the HSC in vivo. The BM is generally considered to be hypoxic (low oxygen tension), but the relationship between local oxygen distribution and the microanatomy of the HSC niche remain poorly defined, in part because of our inability to probe oxygen tension in vivo with cellular resolution. Here we propose to develop molecular imaging technology to enable high-resolution 3D visualization and quantification of local oxygen tension in the BM of live mice. We will use the technology to study if HSC homing and retention in the BM is regulated by local oxygen tension and by hypoxia-inducible factor-1 (HIF-1) dependent cellular response. We will further investigate if anaerobic metabolism is essential for HSC function in vivo. The proposed research requires close collaboration of a multidisciplinary team of investigators with diverse expertise in molecular imaging, optical technology, and stem cell biology. PUBLIC HEALTH RELEVANCE: Narrative Hematopoiesis is the process of blood cell formation from hematopoietic stem cells that reside in the bone marrow. We propose to examine how stem cells respond to oxygen distribution in the bone marrow.