Study of Bone Marrow Failure Caused by B19 Virus Infection
B19病毒感染引起骨髓衰竭的研究
基本信息
- 批准号:8281448
- 负责人:
- 金额:$ 18.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAcuteAnemiaApoptosisApoptosis PromoterApoptoticAutonomous ReplicationBiological AssayBone MarrowCaspaseCell DeathCellsDNA biosynthesisData AnalysesDiseaseDoseEquilibriumErythrocytesErythroid Progenitor CellsErythropoiesisFetal LiverFetusHomeostasisHumanHuman Parvovirus B19Hydrops FetalisHypoxiaImmunityImmunocompromised HostIndividualInfantInfectionIntravenous ImmunoglobulinsKansasKnowledgeLaboratoriesLeadLibrariesLifeMalignant - descriptorMediatingMolecularPTPN11 genePancytopeniaPathogenesisPathway interactionsPatientsPharmaceutical PreparationsPlayProductionProteinsPure Red-Cell AplasiaRecurrenceResearchResearch PersonnelScreening procedureSickle Cell AnemiaSignal PathwaySignal TransductionSymptomsSystemTimeTransplant RecipientsUniversitiesVaccinesViremiaVirusVirus DiseasesWorkbasecaspase-10cytotoxicitydesigndrug candidatedrug developmentexperiencefetal infectionhigh throughput screeningimprovedinsightluminescencenovelresponsesmall moleculesmall molecule libraries
项目摘要
DESCRIPTION (provided by applicant): Parvovirus B19 (B19V) infection causes human bone marrow failure by destroying the bone marrow resident erythroid progenitor cells (EPCs), which support autonomous replication of the virus. In patients with a high demand for erythrocyte production due to high levels of erythrocyte destruction (e.g., sickle-cell disease patients), acute B19V infection can cause transient aplastic crisis. In immunocompromised patients, persistent B19V infection may manifest as pure red-cell aplasia. In the fetus, B19V infection can cause hydrops fetalis, a severe form of anemia. B19V infection induces damage of EPCs, which results in the above bone marrow failures. B19V-infected EPCs undergo cell death with clear apoptotic features. This cell death is induced mainly by high expression of the non-structural 11kDa protein (11kDa) during infection, and involves a caspase cascade triggered by caspase-10. In the proposed research, we aim, firstly, to reveal the molecular mechanism underlying caspase-10- mediated apoptosis in response to 11kDa. To this end, we will determine which apoptotic pathway the extrinsic or the intrinsic activates the initiator caspase-10 during B19V infection-induced apoptosis. As both the apoptotic and anti-apoptotic pathways play key roles in erythropoiesis and the homeostasis of EPCs, we propose to identify the cellular proteins that interact 11kDa and transduce the apoptotic signal in EPCs. Secondly, having recently established a B19V culture system that mimics native B19V infection of human EPCs in bone marrow under hypoxic conditions, we will carry out high throughput screening (HTS) of a library of small molecules (available at the University of Kansas HTS Core Laboratory; contains over 100,000 druglike small compounds) for anti-B19V infection drug candidates. The B19V culture system can generate virus in sufficient quantity for such screening, and the cell death marker can be readily applied to assess B19V infection as a readout. We will use a cell-based luminescent cytotoxicity assay to screen the library. Because B19V vaccine is currently unavailable, and immunocompromised patients would be unable to respond to a vaccine, there are currently no viable treatment options for diminishing the bone marrow failure caused by B19V infection in patients with acute or persistent B19V infection. The study proposed in this application is expected to identify targets for the development of drugs capable of eliminating B19V from human EPCs, and this will ultimately lead to diminished bone marrow failures in these patients. In addition, our analysis of the mechanism underlying apoptosis of EPCs is expected to reveal pathways that may be involved in erythropoiesis or the disruption of erythropoiesis under certain disease conditions.
描述(由申请人提供):细小病毒B19(B19V)感染通过破坏支持病毒自主复制的骨髓驻留红细胞祖细胞(EPC),从而导致人骨髓衰竭。由于高水平的红细胞破坏(例如,镰状细胞疾病患者)对红细胞产生需求较高的患者,急性B19V感染可能会导致短暂性性相位危机。在免疫功能低下的患者中,持续的B19V感染可能表现为纯红细胞性植物。在胎儿中,B19V感染会引起胎儿的水力,这是一种严重的贫血形式。 B19V感染会诱导EPC的损害,这导致上述骨髓失败。 B19V感染的EPC经历细胞死亡,具有明显的凋亡特征。这种细胞死亡主要是由于感染过程中非结构性11KDA蛋白(11KDA)的高表达引起的,并且涉及由caspase-10触发的caspase cascade。在拟议的研究中,首先,我们旨在揭示响应11KDA的caspase-10介导的细胞凋亡的分子机制。为此,我们将确定在B19V感染引起的凋亡过程中,外在或固有的凋亡途径激活了引发剂caspase-10。由于凋亡和抗凋亡途径在红细胞生成和EPC的稳态中都起着关键作用,因此我们建议鉴定相互作用的细胞蛋白,这些细胞蛋白相互作用11KDA并在EPC中转导凋亡信号。其次,最近建立了一个B19V培养系统,该系统在低氧条件下模仿骨髓中人EPC的天然B19V感染,我们将进行高吞吐量筛选(HTS),对小分子库进行高吞吐量筛查(HTS)(可在堪萨斯大学HTS HTS HTS核心实验室中获得100,000次药物类药物的小型化合物的抗抗抗素B19V的抗抗反感。 B19V培养系统可以产生足够数量的筛查病毒,并且可以很容易地应用细胞死亡标记物作为读数评估B19V感染。我们将使用基于细胞的发光细胞毒性测定法来筛选库。由于B19V疫苗目前无法使用,并且免疫功能低下的患者将无法对疫苗反应,因此目前尚无可行的治疗选择可以减少急性或持续性B19V感染患者B19V感染引起的骨髓衰竭。预计在本应用中提出的研究将确定能够从人EPC中消除B19V的药物的靶标,这最终将导致这些患者的骨髓衰竭减少。此外,我们对EPCS潜在凋亡的机制的分析有望揭示可能涉及促红细胞生成的途径或在某些疾病条件下促红细胞生成的途径。
项目成果
期刊论文数量(0)
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Jianming Qiu其他文献
Jianming Qiu的其他文献
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