Collaborative Research: NSF-ANR Mechanisms of Terminal Erythroid Enucleation

合作研究：NSF-ANR 终末红细胞剜除机制

• 批准号: 2210369
• 负责人: Peng Ji
• 金额: $ 35万
• 依托单位: Northwestern University at Chicago
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2210369&HistoricalAwards=false
• 关键词: Collaborative; Research; NSF; ANR; Mechanisms

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.

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，即生成红细胞(RBC)的过程。其目的是阐明骨髓中的机械约束对红系前体细胞核的挤出和脱离的作用。目前人们对这一作用知之甚少，这阻碍了红细胞生成的基础研究取得进展。本项目不仅将促进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来克服无效去核而提高体外红细胞产量提供新的知识。该项目将是第一个连接驱动红系去核的内力和外力，并将细胞的机械传感纳入其中的项目。要揭示内在和外在去核线索的机制，有几个障碍。首先，很难制造一种模拟骨髓拥挤环境的体外设备，具有极小的内皮细胞间间隙，从而允许实时成像去核。其次，由于小间隙中的强相互作用以及跨分子到细胞尺度的力的预测，量化作用力的计算模型具有挑战性。参与该项目的跨学科科学家团队(由三个领导小组组成：西北大学的红细胞生成生物学家、法国马赛国家研究中心的微流体学物理学家和芝加哥伊利诺伊大学的多尺度建模工程师)在克服这些障碍并阐明内在和外在去核信号的机制方面具有独特的地位。该项目将在生物医学领域产生实际影响，例如在稀有血型往往供应有限的输血医学领域。体内红细胞生产的瓶颈是无效的去核，本研究获得的知识将有助于克服这一瓶颈，并有可能给血液供应行业带来革命性的变化。该项目还将产生教育和培训成果，因为从该项目获得的成果和技术将纳入首席调查员教授的课程。一名博士生和两名博士后研究员将通过该项目的支持进行培训。美国/法国的这个合作项目得到了美国国家科学基金会和法国国家科学基金会的支持，其中NSF为美国调查人员提供资金，ANR为法国的合作伙伴提供资金。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。