Developing Choroid Plexus-Based Tools and Drug Screens
开发基于脉络丛的工具和药物筛选
基本信息
- 批准号:9304373
- 负责人:
- 金额:$ 24.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:Alpha CellAlzheimer&aposs DiseaseAnimalsAttentionBiological AssayBiologyBlood CirculationBrainCell LineCell physiologyCell secretionCellsCellular biologyCentral Nervous System DiseasesCerebrospinal FluidClinicalCognitiveDefectDevelopmentDiseaseDrug Delivery SystemsDrug TargetingEnzyme-Linked Immunosorbent AssayEpithelial CellsFenestrated CapillaryFutureGap JunctionsGenerationsGoalsGrowth FactorHormonesHumanHydrocephalusIntercellular FluidLegal patentLibrariesLinkLiteratureMethodsMolecular TargetMusNerve DegenerationNeurodegenerative DisordersPathogenesisPatientsPeripheralPharmacologyPhysiologyPrealbuminPreclinical Drug EvaluationProteinsProtocols documentationProxyPublishingQuality ControlReadinessReagentReproducibilitySchizophreniaScientistSourceSpecificitySpinal CordStrokeStructure of choroid plexusTechnologyTestingTherapeutic InterventionTimeTissuesToxinValidationWaste ProductsWorkanalogassay developmentbaseblood cerebrospinal fluid barriercell typecytokineeffective therapyhigh throughput screeninghuman diseasehuman embryonic stem cellin vitro Assayneglectscale upscreeningstemtool
项目摘要
Although famous for secreting the cerebrospinal fluid (CSF), the choroid plexus has drawn relatively little
attention from basic and clinical scientists. Every day, human choroid plexus epithelial cells (CPECs) secrete
about two cups of protein-rich CSF, which clears out waste products from and delivers beneficial molecules to
every cell in the brain and spinal cord. CPEC defects have been implicated in a large number of major CNS
disorders, including hydrocephalus, psychiatric conditions, and neurodegenerative diseases. However, almost
all of the literature related to CPEC biology and disease is descriptive due to a lack of CPEC-targeted tools.
Importantly, if such tools existed, delivery of compounds to CPECs - in either experimental animals or patients
- is straightforward, because CPECs exchange freely with the peripheral circulation. This greatly simplifies drug
delivery and strengthens the appeal of CPECs as a new target for CNS studies and disease therapies. Despite
this appeal, CPEC-targeted drug screens have not been possible due to difficulties in propagating and deriving
them in culture. However, we recently developed a method for generating derived CPECs (dCPECs) from
mouse and human embryonic stem cells. This method provides, for the first time, a scalable means to produce
dCPECs in the large numbers required for high-throughput screening (HTS).
In this R21 proposal, we combine the dCPEC technology inventor with experts in assay development
and drug screening to develop a high-throughput dCPEC screening platform. In preliminary studies, we
describe dCPEC generation, candidate cell lines to be screened for HTS compatibility, and a sensitive 96-well
ELISA for secreted human TTR, an ideal proxy for CPEC secretion and an important molecular target in its
own right. The TTR ELISA will be converted into an HTS-compatible AlphaLISA, which will be used for a pilot
screen to determine assay readiness. Hits and analogs from the pilot screen will then be screened and
validated via "testing funnels" that include new and already-established assays of CPEC function, mechanism,
and specificity. This validated high-throughput dCPEC platform will set the stage for full-scale screening
proposals to generate first-in-class tool and therapy leads for a brand-new CPEC-based biomedicine.
虽然以分泌脑脊液(CSF)而闻名,脉络膜丛相对较少
项目成果
期刊论文数量(0)
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