CAREER: Building bone marrow

1254738 HarleyHematopoiesis是一个过程，其中所有的身体的血液和免疫细胞是从少量的造血干细胞（HSC）产生的。这些事件发生在骨髓的独特部分，称为“龛”。指导HSC行为所需的遗传信息，如长期不活动，自我更新或分化以产生血液和免疫细胞，包含在其DNA中，但需要来自小生境的外部信号来触发这些事件。虽然HSC负责每天产生近1万亿个造血细胞，如血小板和免疫细胞，但这一过程中的突变导致造血病理学，如白血病。然而，很难在骨髓中研究这些事件。该项目的长期目标是建立一种人工骨髓，提供正确的小生境信号序列，以在实验室中培养HSC。这样的工具将是变革性的，因为它将允许人们解开定义HSC小生境的线索网络，以及工程变异，以协助一系列造血和癌症生物学研究。为此，该小组创建了一个骨髓生物芯片平台，将HSC小生境的复杂性降低到一系列可管理的离散信号，我们可以在三维生物材料中选择性地定义这些信号。这种生物芯片可以从骨髓中分离出少量的HSC，以确定的增量操纵这些细胞周围的小生境信号，并跟踪它们的反应。在这个项目中，我们将绘制三种重要的生态位信号的组合-骨髓的结构组成，支持性生态位细胞和生物分子线索-如何影响两个关键行为，自我更新与分化的启动。这些知识对于确定如何将小生境信号工程化到生物材料中以控制HSC活性的所有阶段至关重要。通过一个协调的研究和教育计划，该项目将直接支持一些重要的推广计划。将利用针对小学、中学和本科生的外联工作来扩大对科学和工程的参与。在这个项目中开发的工具将作为正在进行的和未来的研究项目在免疫学，生物学，工程学科的融合的基础。

1254738 HarleyHematopoiesis is the process where all the body's blood and immune cells are generated from a small number of hematopoietic stem cells (HSCs). These events take place in unique parts of the bone marrow termed 'niches'. The genetic information required to direct HSC behaviors such as long-term inactivity, self-renewal, or differentiation to produce blood and immune cells is contained within its DNA, but external signals from the niche are required to trigger these events. And while HSCs are responsible for producing nearly one trillion hematopoietic cells per day such as platelets and immune cells, mutations in this process are responsible for hematopoietic pathologies such as leukemia. However, it is difficult to study these events inside the bone marrow. The long-term goal of this project is to build an artificial bone marrow that provides the correct sequence of niche signals to grow HSCs in the laboratory. Such a tool would be transformative because it would allow one both untangle the web of cues that define HSC niches as well as engineer variants to assist a range of hematopoietic and cancer biology studies. To that end, the group has created a bone marrow biochip platform that reduces the complexity of HSC niches to a manageable series of discrete signals that we can selectively define within a threedimensional biomaterial. This biochip allows to isolate small numbers of HSCs from the bone marrow, manipulate the niche signals surrounding these cells in defined increments, and track their response. This project we will chart how combinations of three important classes of niche signals -- the structural make-up of the bone marrow, supportive niche cells, and biomolecule cues -- impact two critical behaviors, self-renew versus the initiation of differentiation. Such knowledge will be critical for defining how niche signals can be engineered into a biomaterial to control all phases of HSC activity. Through a coordinated research and educational plan, this project will directly support a number of critical outreach programs. Outreach efforts targeting early elementary, secondary, and undergraduate students will be used to broaden participation in science and engineering. Tools developed during this project will serve as the foundation for ongoing and future research projects at the confluence of immunology-biology-engineering disciplines.