Collaborative Research: NSF-ANR Mechanisms of Terminal Erythroid Enucleation

该奖项旨在描述哺乳动物红细胞生成过程中去核的物理机制。目的是阐明骨髓中的机械约束对红细胞前体细胞核的挤压和脱离的作用。这一作用目前知之甚少，这阻碍了红细胞生成基础研究的进展。该项目不仅将加深我们对红细胞去核的基本认识，而且将为通过工程机械环境改善体外红细胞生成以克服去核无效提供新的知识。这个项目将是第一个将驱动红细胞去核的内部和外部力量联系起来，并结合细胞的机械传感。有几个障碍揭示内在和外在的去核线索的机制。首先，很难制造一种体外装置来模拟骨髓的拥挤环境，其内皮间隙极小，可以实时成像去核。其次，由于小间隙中的强相互作用和跨分子到细胞尺度的力预测，用于量化力的计算建模具有挑战性。该项目的跨学科科学家团队（由三个主要小组组成：西北大学红细胞生成生物学家，法国马赛CNRS微流体物理学家，伊利诺伊大学芝加哥分校多尺度建模工程师）具有独特的优势，可以克服这些障碍，阐明内在和外在去核线索的机制。该项目将对生物医学领域产生实际影响，例如输血医学，因为稀有血型往往供应有限。体内红细胞生产的瓶颈是无效的去核，从本研究中获得的知识将有助于克服这一瓶颈，并有可能彻底改变血液供应行业。该项目还将产生教育和培训成果，因为从该项目中获得的成果和技术将纳入首席研究员教授的课程。本项目将培养1名博士生和2名博士后。这个美国/法国合作项目由美国国家科学基金会和法国国家研究机构支持，其中美国国家科学基金会资助美国研究人员，法国国家研究机构资助法国合作伙伴。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This award aims to describe the physical mechanisms at play in enucleation during mammalian erythropoiesis, which is the process of generation of red blood cells (RBCs). The objective is to elucidate the role of the mechanical constraints in the bone marrow on the extrusion and detachment of the nucleus of the erythroid precursor. This role is currently poorly understood, which holds back progress in fundamental studies of erythropoiesis. This project will not only advance our fundamental understanding of erythroid enucleation but provide new knowledge for improving in vitro red blood cell production by engineering mechanical environments to overcome ineffective enucleation. This project will be the first to connect the internal and external forces that drive erythroid enucleation, and to incorporate mechanosensing of the cell. There are several barriers to reveal the mechanisms of intrinsic and extrinsic enucleation cues. First, it is difficult to fabricate an in vitro device that mimics the crowded environment of the bone marrow with extremely small inter-endothelial gaps that allows live imaging of enucleation. Second, the computational modeling for quantifying forces is challenging due to the strong interactions in small gaps and the prediction of forces across molecular to cellular scales. The interdisciplinary team of scientists in this project (consisting of three leading groups: a biologist in erythropoiesis at Northwestern University, a physicist in microfluidics in CNRS Marseille, France, and an engineer in multiscale modeling at the University of Illinois at Chicago) is uniquely positioned to overcome such barriers and elucidate the mechanisms of intrinsic and extrinsic enucleation cues.This project will have practical impact in the biomedical field, such as transfusion medicine in which rare blood types often have limited supplies. The bottleneck of in vivo RBC production is the ineffective enucleation, and the knowledge obtained from this study will help overcome this bottleneck and could potentially revolutionize the industry of blood supply. The project will also have educational and training outcomes, as results and techniques obtained from this project will be incorporated into courses the Principal Investigators teach. One PhD student and two postdoctoral fellows will be trained through the support of this project. This collaborative US/France project is supported by the US National Science Foundation and the French Agence Nationale de la Recherche, where NSF funds the US investigators and ANR funds the partner in France.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.