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3D Models of Engineered Human iPS Cells to Investigate Neurotropic Virus Infections

3D Models of Engineered Human iPS Cells to Investigate Neurotropic Virus Infections
用于研究嗜神经病毒感染的工程化人类 iPS 细胞 3D 模型
批准号:
9903201
负责人:
Lee Gehrke
金额:
$171.63万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-04-01 至 2022-03-31
关键词:
3-DimensionalAddressAdoptedAnimal ModelAntiviral AgentsArchitectureAstrocytesAwarenessBasic ScienceBiologicalBiological ModelsBiomedical ResearchCRISPR screenCell modelCellsCellular biologyCentral Nervous System InfectionsCerebrumCollaborationsCommunicable DiseasesDangerousnessDataDengue VirusDevelopmentDiseaseEastern Equine EncephalomyelitisEmbryoEthicsFlavivirusFlavivirus InfectionsFunctional disorderGenesGeneticGenetic ScreeningGoalsGrowthGuillain-Barré SyndromeHealth SciencesHumanHuman EngineeringHuman GeneticsIn VitroIndividualInfectionInstitutesInvestmentsKnock-outMassachusettsMethodsMicrocephalyMicrogliaModelingMolecularNational Institute of Allergy and Infectious DiseaseNeuronsNewspapersOligodendrogliaOrganoidsPharmaceutical PreparationsPhenotypePhysiologicalPhysiologyPoliticsPopulationPositioning AttributeProblem SolvingReagentResearchResearch PersonnelResearch Project GrantsScienceSiteSystemTechnologyTestingTherapeuticTissue EngineeringTissue ModelTissuesTransformed Cell LineTranslatingVenezuelan Equine EncephalomyelitisVesicular stomatitis Indiana virusVirusVirus DiseasesWest Nile virusWestern Equine EncephalomyelitisWorkWritingYouthZika Virusbasecell dimensioncell typedrug candidatedrug developmentdrug efficacydrug testingembryonic stem cellengineered stem cellsgenetic approachglobal healthhealth economicshuman diseasehuman embryonic stem cellhuman tissueimprovedinduced pluripotent stem cellinfectious disease modelinterestmeetingsmembernerve stem cellneurotropic virusnovelpathogenprofessorrelating to nervous systemresponsescientific literacystemstem cell differentiationstem cellstherapeutic evaluationthree-dimensional modelingtissue regenerationtwo-dimensionalvirologyvirus tropism

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中文摘要
翻译
目前迫切需要改进人体组织模型来研究传染病。动物模型
英文摘要
There is a critical need for improved human tissue models to study infectious diseases. Animal models often  fail to reproduce human physiology, and are similarly poor predictors of drug efficacy when translated to  humans. This proposal describes the MIT Center for Human Tissue Models for Infectious Diseases  (MIT.HTMID), which will focus on two dimensional human neural cells and three dimensional human cerebral  organoids to study virus infections. The project is sited entirely at The Massachusetts Institute of Technology.  The three investigators are: Lee Gehrke (Virology and Infectious Diseases), Rudolf Jaenisch (Tissue  Engineering, Cell Biology, and Stem Cells) and David Sabatini (Genetics and Screening Technologies). The  Center will also include three Cores; that is, Administrative, Virology, and Human Cells and Tissues. The  themes of the two interrelated Research Projects of this U19 proposal are: ​Project 1: ​Human tissue models to  study infectious diseases: Human 2D and 3D neural cultures for studying virus tropism and infection  phenotypes, and ​Project 2: ​Use of 2D cultures and 3D organoids to identify candidate antiviral compounds; to  use genetic approaches to identify and validate host genes that promote or protect against flavivirus infection​.  The experimental use of organoids is significant because the three dimensional architecture and differentiation  from embryonic stem (ES) cells and induced pluripotent stem (iPS) cells provide near­physiological functions in  tissue organization, tissue renewal, and responses to pathogen infections. Indeed, human organoids have  been generated for a wide range of tissues and uses in studying development and diseases, including virus  infections. The project will compare the infections of five different neural or microglial cell types (neuronal  progenitors, neurons, oligodendrocytes, astrocytes, microglia) with three flaviviruses (Zika Virus, West Nile  Virus, or Dengue virus). The research goals of MIT.HTMID address the Zika virus global health crisis, toward  understanding how related flaviviruses can cause very different diseases, including microcephaly and Guillain  Barre Syndrome. The virus work will be extended beyond flaviviruses to include other neurotropic viruses; that  is, pseudotyped vesicular stomatitis viruses (VSV) that carry the envelopes of select agent encephalitic viruses  (Eastern Equine Encephalitis, Western Equine Encephalitis, and Venezuelan Equine Encephalitis).  We will  use cell and molecular methods to define and compare the infection phenotypes of the cells and viruses.  Tissue engineering and genetics will be combined by performing CRISPR­Cas9 screens to identify genes that  regulate or are regulated by virus infection, and then generating “knockout” organoids to test function in a  three­dimensional tissue. The organoid human tissue model will also be used to evaluate a number of antiviral  compounds to validate its potential use as a drug testing platform. If successful, this Center will yield significant  new data and be an integral component of a network of Human Tissue Models for Infectious Diseases.
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Administrative Core: 3D Models of Engineered Human iPS Cells to Investigate Neurotropic Virus Infections
Human Cells and Tissues Core: 3D Models of Engineered Human iPS Cells to Investigate Neurotropic Virus Infections
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