Salivary gland tissue chip designed to screen preventative drugs for radiation-induced xerostomia
唾液腺组织芯片设计用于筛选辐射引起的口干症的预防药物
基本信息
- 批准号:10304851
- 负责人:
- 金额:$ 3.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-15 至 2022-06-28
- 项目状态:已结题
- 来源:
- 关键词:Acinar CellAddressAmifostineAmylasesBiochemicalBiological AssayBiological MarkersCalcium SignalingCaspaseCell CommunicationCell Culture TechniquesCell physiologyCellsClinicalCommunitiesConsumptionCuesDental cariesDevelopmentDigestionDiseaseDrug ScreeningElementsEncapsulatedExtracellular Matrix ProteinsFDA approvedFutureGamma-H2AXGrowthHydrogelsImageImpairmentIn VitroInstructionMaintenanceMatrix MetalloproteinasesMeasuresMethodsMicrobubblesMucinsMuramidaseMusParacrine CommunicationPatientsPeptidesPharmaceutical PreparationsPhenotypePreclinical TestingPreventionPreventive screeningPreventive treatmentProteinsPublic HealthRadiationRadiation induced damageRadiation therapyRadiation-Protective AgentsResearchRiskSalivarySalivary Gland TissueSalivary GlandsSavingsShapesSourceStructureSyndromeSystemTechniquesTechnologyTestingTimeTissue MicroarrayTissuesVomitingWorkXerostomiaautocrinebasebody systemchromatin immunoprecipitationdesigndrug candidatedrug preservationethylene glycolgamma irradiationhead and neck cancer patienthigh throughput screeninghigh-throughput drug screeningimprovedin vitro Modelin vivoirradiationmimeticsnovelnovel therapeuticsoral infectionparacrinepolydimethylsiloxanepreservationpreventradiation effectradiation responsescreeningside effecttool
项目摘要
Radiation-induced xerostomia (dry mouth syndrome) is a common side effect in head and neck cancer
patients caused by off-target effects of radiation therapy that damage the salivary glands. This condition leads
to hyposalivation, oral infections, tooth decay, difficulty speaking, and impaired digestion, among other
complications, in ~40% of patients. While amifostine, an FDA-approved drug to prevent this condition, can be
administered to patients, its clinical usefulness is limited, as severe vomiting in many patients requires
discontinuing treatment. Discovery of alternative drugs is hindered by a lack of relevant in vitro models, as
salivary gland cells rapidly lose the organization and secretory function when removed from the body.
To address this technological challenge, we propose the use of a unique system combining
microbubble (MB) array technology with poly(ethylene glycol) (PEG) hydrogels to create a favorable
microenvironment for salivary gland tissue mimetic growth in vitro. MBs are separated spherical cavities with
200 µm openings and ~40 nL volume formed in polydimethylsiloxane (PDMS). MBs are arranged in an array-
based format for high-throughput screening and the unique spherical shape has been shown to concentrate
paracrine/autocrine factors to allow cells to condition their own microenvironment. Matrix metalloproteinase
(MMP)-degradable PEG macrogels (1 mm x 5 mm discs) have been shown to promote tissue mimetic
structure and maintenance of biomarker expression through encouraging cell-cell and cell-matrix interactions.
The central hypothesis is that the combination of these two techniques will improve the in vitro
microenvironment of salivary gland tissue mimetics and provide an effective platform for high-throughput
screening of preventative drugs for radiation-induced xerostomia. To address this hypothesis, three aims have
been identified. In-chip assays will be developed to analyze the secretory function of salivary gland tissue
mimetics in MBs (amylase, mucins, lysozyme; Aim 1A) and their response to radiation damage (caspase,
γH2AX, PrestoBlue™, EdU; Aim 1B) by adapting macroscale (e.g. 96-well plate) assays/characterization
techniques. Aim 2 will identify proteins/peptides that provide instructive cues for promoting secretory function
and organization similar to native salivary gland tissue, as measured by assays developed in Aim 1A.
Preliminary testing of radioprotective drugs will occur in Aim 3, where a selected list of radioprotective drugs
will be screened through the MB-hydrogel system and compared to amifostine, the currently approved therapy.
This project is significant for public health, as it will provide important preclinical testing for new drugs to
prevent radiation-induced xerostomia. It will impact the research community by providing a unique high-
throughput drug screening platform that can be adapted for other tissues.
辐射引起的口干症(口干综合症)是头颈癌的常见副作用
由于放射治疗的脱靶效应损害唾液腺而引起的患者。这种情况导致
唾液分泌不足、口腔感染、蛀牙、说话困难和消化不良等
约 40% 的患者出现并发症。而氨磷汀(amifostine)是 FDA 批准的一种预防这种情况的药物,可以
给予患者,其临床用途有限,因为许多患者严重呕吐需要
停止治疗。由于缺乏相关的体外模型,替代药物的发现受到阻碍,因为
唾液腺细胞从体内取出后迅速失去组织和分泌功能。
为了应对这一技术挑战,我们建议使用一种独特的系统,结合
微泡(MB)阵列技术与聚(乙二醇)(PEG)水凝胶创建有利的
唾液腺组织体外模拟生长的微环境。 MB 是分离的球形空腔
在聚二甲基硅氧烷 (PDMS) 中形成 200 µm 开口和约 40 nL 体积。 MB 排列成数组 -
基于高通量筛选的格式和独特的球形形状已被证明可以集中
旁分泌/自分泌因子使细胞能够调节自己的微环境。基质金属蛋白酶
(MMP)-可降解 PEG 大凝胶(1 mm x 5 mm 圆盘)已被证明可以促进组织模拟
通过鼓励细胞-细胞和细胞-基质相互作用来构建和维持生物标志物表达。
中心假设是这两种技术的结合将改善体外
唾液腺组织模拟物的微环境,并为高通量提供有效的平台
筛选辐射引起的口干症的预防药物。为了解决这个假设,我们有三个目标
已被识别。将开发芯片内分析方法来分析唾液腺组织的分泌功能
MB 中的模拟物(淀粉酶、粘蛋白、溶菌酶;Aim 1A)及其对辐射损伤的反应(半胱天冬酶、
γH2AX、PrestoBlue™、EdU;目标 1B) 通过采用宏观(例如 96 孔板)测定/表征
技术。目标 2 将鉴定为促进分泌功能提供指导性线索的蛋白质/肽
和组织与天然唾液腺组织相似,通过目标 1A 中开发的测定进行测量。
辐射防护药物的初步测试将在目标 3 中进行,其中选定的辐射防护药物清单
将通过MB-水凝胶系统进行筛选,并与目前批准的疗法amifostine进行比较。
该项目对公共卫生具有重要意义,因为它将为新药提供重要的临床前测试
预防辐射引起的口干症。它将通过提供独特的高水平影响研究界
可适用于其他组织的高通量药物筛选平台。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Optimizing Soluble Cues for Salivary Gland Tissue Mimetics Using a Design of Experiments (DoE) Approach.
- DOI:10.3390/cells11121962
- 发表时间:2022-06-18
- 期刊:
- 影响因子:6
- 作者:Piraino, Lindsay R.;Benoit, Danielle S. W.;DeLouise, Lisa A.
- 通讯作者:DeLouise, Lisa A.
Encapsulation of Primary Salivary Gland Acinar Cell Clusters and Intercalated Ducts (AIDUCs) within Matrix Metalloproteinase (MMP)-Degradable Hydrogels to Maintain Tissue Structure and Function.
- DOI:10.1002/adhm.202101948
- 发表时间:2022-04
- 期刊:
- 影响因子:10
- 作者:Song Y;Sharipol A;Uchida H;Ingalls MH;Piraino L;Mereness JA;Moyston T;DeLouise LA;Ovitt CE;Benoit DSW
- 通讯作者:Benoit DSW
Development of a functional salivary gland tissue chip with potential for high-content drug screening.
- DOI:10.1038/s42003-021-01876-x
- 发表时间:2021-03-19
- 期刊:
- 影响因子:5.9
- 作者:Song Y;Uchida H;Sharipol A;Piraino L;Mereness JA;Ingalls MH;Rebhahn J;Newlands SD;DeLouise LA;Ovitt CE;Benoit DSW
- 通讯作者:Benoit DSW
Salivary Gland Tissue Engineering Approaches: State of the Art and Future Directions.
- DOI:10.3390/cells10071723
- 发表时间:2021-07-08
- 期刊:
- 影响因子:6
- 作者:Piraino LR;Benoit DSW;DeLouise LA
- 通讯作者:DeLouise LA
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