Collaborative Research NSF-ANR: Mechanisms of Terminal Erythroid Enucleation

NSF-ANR 合作研究：终末红细胞剜除机制

• 批准号: 2210366
• 负责人: Zhangli Peng
• 金额: $ 25万
• 依托单位: University of Illinois 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=2210366&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，这是红细胞（RBC）的生成过程。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分离的作用。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。该项目不仅将推进我们对红细胞去核的基本理解，而且将为通过工程机械环境来克服无效的去核来改善体外红细胞生产提供新的知识。该项目将是第一个连接驱动红细胞去核的内部和外部力量，并结合细胞的机械传感。揭示内源性和外源性去核线索的机制存在一些障碍。首先，很难制造一种体外装置，该装置模仿骨髓的拥挤环境，具有允许摘除的实时成像的极小的内皮间间隙。其次，由于小间隙中的强相互作用以及分子到细胞尺度上的力预测，用于量化力的计算建模是具有挑战性的。 这个项目中的跨学科科学家团队（由三个领导小组组成：西北大学红细胞生成生物学家，法国国家科学研究中心马赛微流体物理学家，和芝加哥伊利诺斯大学多尺度建模工程师）是唯一的定位，以克服这些障碍，并阐明机制的内在和外在的去核线索。这个项目将有实际的影响，生物医学领域，如输血医学，其中稀有血型通常供应有限。体内红细胞生产的瓶颈是无效的去核，从这项研究中获得的知识将有助于克服这一瓶颈，并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，因为从该项目获得的结果和技术将纳入主要研究者教授的课程。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。 这个美国/法国合作项目得到了美国国家科学基金会和法国国家研究机构的支持，NSF为美国的研究人员提供资金，ANR为法国的合作伙伴提供资金。该奖项反映了NSF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。

项目成果

Polyurethane Culture Substrates Enable Long-Term Neuron Monoculture in a Human in vitro Model of Neurotrauma.

• DOI: 10.1089/neur.2023.0060
• 发表时间: 2023
• 期刊: NEUROTRAUMA REPORTS
• 影响因子: 2.4
• 作者: Mitevska, Angela;Santacruz, Citlally;Martin, Eric J.;Jones, Ian E.;Ghiacy, Arian;Dixon, Simon;Mostafazadeh, Nima;Peng, Zhangli;Kiskinis, Evangelos;Finan, John D.
• 通讯作者: Finan, John D.

Physical mechanisms of red blood cell splenic filtration

• DOI: 10.1073/pnas.2300095120
• 发表时间: 2023-10-31
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Moreau, Alexis;Yaya, Francois;Peng, Zhangli
• 通讯作者: Peng, Zhangli

Analytical theory for a droplet squeezing through a circular pore in creeping flows under constant pressures

• DOI: 10.1063/5.0156349
• 发表时间: 2023-08-01
• 期刊: PHYSICS OF FLUIDS
• 影响因子: 4.6
• 作者: Tang, Zhengxin;Yaya, Francois;Peng, Zhangli
• 通讯作者: Peng, Zhangli