权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

EAGER: Interactions of Engineered Nanomaterials with Red Blood Cells in Health and Disease

EAGER：工程纳米材料与红细胞在健康和疾病中的相互作用

基本信息

批准号：
1903568
负责人：
Douglas Goetz
金额：
$ 13.5万
依托单位：
Ohio University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-15 至 2023-04-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1903568&HistoricalAwards=false
关键词：
EAGER Interactions Engineered Nanomaterials Red

项目摘要

Studies have demonstrated that some nanomaterials, depending on exposure, composition, and properties, can disrupt the plasma membrane, a lipid bilayer that surrounds all cells, thereby causing cell toxicity. However, the role of the individual leaflets of the plasma membrane in regulating the disruptive effects of nanomaterials is not known. The plasma membrane is composed of two leaflets: an inner leaflet facing the cell and an outer leaflet facing the outside environment. Red blood cells provide an ideal model to study plasma membrane-nanoparticle interactions due to being one of the few cells for which the lipid composition of both leaflets is known. In addition, disruption of red blood cells by nanomaterials can be easily tracked by the release of hemoglobin, which has a distinct red color. The investigator has recently shown that disruption of red blood cells by nanoparticles is dependent on the lipid composition of the outer leaflet with little to no contribution from the inner leaflet. In this proposal, the investigator will examine how the lipid composition of the outer leaflet regulates nanoparticle-membrane interactions. To this aim, the investigator will study the interactions of a set of engineered nanoparticles with healthy and diseased red blood cells in which the outer leaflet lipid composition is altered. Chronic myeloid leukemia, a form of blood cancer, will be used as the diseased model. This disease does not commonly show symptoms in its early phases but induces changes in the lipid composition of the outer leaflet of red blood cells. Completion of this project provides benefits to society through 1) elucidating the role of the outer leaflet lipids in regulating nanoparticle toxicity, 2) providing information on the toxicity of nanoparticles to red blood cells in healthy vs. leukemic individuals, and 3) the development of a rapid screening assay for chronic myeloid leukemia. This project will involve undergraduate students in research, facilitate hands-on nanotechnology education, and educate the public through demonstrations focused on nanotechnology in a local non-profit.Nanomaterials, depending on exposure and physicochemical properties, can disrupt the cell plasma membrane. The plasma membrane is an asymmetric lipid bilayer and the composition of lipids in the outer leaflet (facing the outside environment) is different from the lipids in the inner leaflet (facing the cytoplasm). The investigator 's previous research, using engineered silica nanoparticles and vesicles that mimic each leaflet of the plasma membrane of red blood cells, has shown that the lipid composition of the outer leaflet is the primary regulator of nanoparticle-induced membrane damage. In this project, the investigator will examine the interactions of engineered nanoparticles with the plasma membrane of healthy and diseased red blood cells in which membrane lipid asymmetry is disrupted, to examine how the lipid composition of the outer leaflet regulates nanoparticle-cell membrane interactions. Chronic myeloid leukemia, a form of blood cancer, will be used as the diseased model. This disease is asymptomatic in its early phases but is known to disrupt the asymmetry of the plasma membrane in red blood cells. In this project, the PI will first investigate how engineered silica nanoparticles bind to, deform, or disrupt healthy vs. leukemic red blood cells. The PI will then characterize the outer leaflet lipid composition of healthy and leukemic red blood cells to elucidate how the outer leaflet lipids regulate nanoparticle-cell membrane interactions. This project is high risk-high payoff. While significant differences are expected in nanoparticle-induced membrane disruption in healthy vs. diseased red blood cells, which have different outer leaflet lipid compositions, there is the risk distinguishing and characterizing these differences is extremely difficult. However, if significant differences are observed, this project could be the stepping-stone for the use of nanoparticles for screening of diseases in which the plasma membrane lipid composition is altered. This is a transformative approach, which can lead to a plethora of novel screening assays in the future. This project will also provide new information concerning the biological behavior of nanomaterials. Successful conclusion of this research will shed light on the role of nanomaterial physicochemical properties which induce damage in the membranes of mammalian cells and characterize differences in nanoparticle-induced toxicity for different cells which are a function of the lipid composition of the outer leaflet of cell membranes.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.

研究表明，根据暴露、组成和性质的不同，一些纳米材料可以破坏质膜，质膜是包围所有细胞的脂质双层，从而导致细胞毒性。然而，质膜的单个小叶在调节纳米材料的破坏效应中的作用尚不清楚。质膜由两片小叶组成：面向细胞的内叶和面向外界环境的外叶。红细胞是为数不多的已知两叶脂质成分的细胞之一，为研究质膜-纳米颗粒的相互作用提供了理想的模型。此外，纳米材料对红细胞的破坏可以很容易地通过血红蛋白的释放来追踪，血红蛋白具有明显的红色。这位研究人员最近表明，纳米颗粒对红细胞的破坏取决于外叶的脂肪成分，而内叶的贡献很小或没有贡献。在这项提案中，研究人员将研究外叶的脂质成分如何调节纳米颗粒-膜的相互作用。为此，研究人员将研究一组经过工程处理的纳米颗粒与健康和患病的红细胞之间的相互作用，在这些红细胞中，外叶的脂质成分发生了变化。慢性粒细胞白血病是一种血癌，将被用作疾病模型。这种疾病通常在早期阶段不会出现症状，但会导致红细胞外层小叶的脂肪成分发生变化。该项目的完成将通过以下方式为社会带来好处：1)阐明外叶脂肪在调节纳米颗粒毒性方面的作用；2)提供有关纳米颗粒对健康和白血病患者红细胞毒性的信息；3)开发一种慢性髓系白血病快速筛查方法。这个项目将让本科生参与研究，促进实践纳米技术教育，并通过在当地非营利性组织中专注于纳米技术的演示来教育公众。纳米材料可以破坏细胞膜，这取决于暴露和物理化学性质。质膜是一个不对称的脂质双层，外叶(面向外界)的脂质组成与内叶(面向细胞质)的脂类组成不同。研究人员S之前的研究使用了经过改造的二氧化硅纳米颗粒和模拟红细胞膜每一片质膜的囊泡，表明外叶的脂质成分是纳米颗粒诱导的膜损伤的主要调节因素。在这个项目中，研究人员将检查工程纳米颗粒与健康和患病红细胞膜的相互作用，其中膜脂不对称被破坏，以检查外叶的脂质成分如何调节纳米颗粒-细胞膜的相互作用。慢性粒细胞白血病是一种血癌，将被用作疾病模型。这种疾病早期无症状，但已知会破坏红细胞膜的不对称性。在这个项目中，PI将首先研究工程二氧化硅纳米颗粒如何与健康的白血病红细胞结合、变形或破坏。然后，PI将表征健康和白血病红细胞的外叶脂类成分，以阐明外叶脂类如何调节纳米颗粒-细胞膜相互作用。这个项目是高风险-高回报的。虽然预计纳米颗粒对健康和患病红细胞的膜破坏有显著差异，但存在区分和表征这些差异的风险，因为健康红细胞和患病红细胞具有不同的外叶脂肪成分。然而，如果观察到显著的差异，该项目可能成为使用纳米颗粒筛查质膜脂质成分改变的疾病的垫脚石。这是一种变革性的方法，未来可能会产生过多的新的筛查分析方法。该项目还将提供有关纳米材料生物行为的新信息。这项研究的成功结束将阐明纳米材料的物理化学性质在哺乳动物细胞膜损伤中的作用，并表征纳米颗粒对不同细胞诱导的毒性差异，这是细胞膜外层小叶的脂质组成的函数。该奖项反映了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。