Functional and Anatomical Characterization of the Hematopoietic Stem Cell Niche

描述（由申请人提供）： 造血干细胞（HSC）是骨髓中唯一具有分化为所有血液谱系和自我更新能力的细胞。这两种特性允许造血稳态的适当维持，但HSC内的遗传异常可导致严重的负面后果，如免疫缺陷、贫血或白血病。因为用正常的HSC替换遗传异常的HSC可以纠正许多这些疾病，所以了解如何最好地实现这种交换，同时最大限度地降低患者的风险至关重要。骨髓移植成功的最重要参数之一是供者HSC移植的足够数量的适当骨髓微环境的可用性。下面概述的研究方案描述了一系列经典和技术新颖的方法，旨在更好地了解HSC与其所在的高度特异性骨髓微环境的功能相互作用，以及通过利用这些动态相互作用进行治疗干预的潜力。预计对这一领域的重大贡献将使我能够在未来3年内过渡到一个独立的教师职位。 具体目标： 目的1：表征稳态条件下HSC龛排空和再填充的动力学、幅度和治疗潜力。 目的2：分离和鉴定HSC支持的小生境细胞。 目的3：研究肝星状细胞在体内归巢和植入的定位和可视化。相关性：造血干细胞是存在于骨髓中的一种显著的细胞类型，负责产生所有红细胞和白色血细胞。为了使它们适当地发挥功能，它们必须驻留在骨髓内的特定区域或壁龛中。本提案的目的是更好地描述这些小生境的特性，并确定如何最好地利用这些小生境进行骨髓移植。

DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSCs) are the only cells within the bone marrow that possess the ability to both differentiate to all blood lineages and to self-renew for life. These two properties allow for the proper maintenance of hematopoietic homeostasis, but genetic abnormalities within HSCs can lead to profound negative consequences such as immunodeficiency, anemia, or leukemia. Because the replacement of genetically abnormal HSCs with normal HSCs can correct many of these diseases, it is of critical importance to understand how best to achieve such an exchange while minimizing risk to the patient. One of the most important parameters for the success of bone marrow transplantations is the availability of sufficient numbers of appropriate bone marrow microenvironments for donor HSCs to engraft. The research proposal outlined below describes a series of both classical and technologically novel approaches designed to better understand the functional interactions of HSCs with the highly specific bone marrow microenvironments in which they reside and the potential for therapeutic intervention by capitalizing upon these dynamic interactions. It is anticipated that significant contributions to this field will allow me to transition to an independent faculty position within the next 3 years. Specific Aims: Aim 1: To characterize the kinetics, magnitude, and therapeutic potential of HSC niche emptying and refilling under steady state conditions. Aim 2: To isolate and characterize HSC-supportive niche cells. Aim 3: To localize and visualize HSC homing and engraftment in vivo. Relevance: The hematopoietic stem cell is a remarkable cell type that exists within the bone marrow and is responsible for the production of all red and white blood cells for life. In order for them to function appropriately, they must reside within specific areas, or niches, within the bone marrow. The goal of this proposal is to better characterize the properties of these niches and to determine how best to utilize these niches for bone marrow transplantation.