Monitoring graft responses to the transplant niche in allogeneic cell replacement therapy
监测同种异体细胞替代疗法中移植物对移植生态位的反应
基本信息
- 批准号:10822197
- 负责人:
- 金额:$ 87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-06 至 2025-08-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAcuteAdaptive Immune SystemAddressAdverse eventAllogenicAnimal ModelAnti-Inflammatory AgentsBeta CellBindingBiologyBiosensing TechniquesBiosensorBlood GlucoseC-PeptideCell Surface ProteinsCell TherapyCell TransplantationCellsClinicalCytoprotectionDevelopmentDiabetes MellitusEngraftmentEnvironmentFailureFeedbackFutureGoalsHealthImmuneImmune systemImmunosuppressionIn VitroInfectionInflammationInflammatoryInflammatory ResponseInfusion proceduresInnate Immune SystemInsulinInsulin-Dependent Diabetes MellitusInterventionIslets of Langerhans TransplantationLeadLearningLocationMeasurableMeasuresMethodologyMethodsMicroRNAsMissionMonitorOperative Surgical ProceduresOrganOrgan TransplantationOrganoidsPatientsPhasePhysiologicalPre-Clinical ModelProceduresProcessResourcesSignal InductionSignal TransductionSiteSmall Business Innovation Research GrantStressSystemTechnologyTestingTherapeutic InterventionTimeTissue GraftsTissue TransplantationTransplantationassaultautoimmune pathogenesiscell replacement therapycell typecohortcommercializationcyanine dye 5cytokinedesigndetection platformexperiencehuman stem cellsimmune activationimprovedimproved outcomein vivoin vivo monitoringisletlead candidatemanufacturenanoengineeringnanoparticlenanoprobenanosensorsnovelnovel strategiespost-transplantreplacement tissueresponsescale upsensorstem cell therapystem cellssubcutaneoussuccesstherapy designtool
项目摘要
Project Summary/Abstract
Patients living with Type 1 Diabetes regulate their blood glucose through daily exogenous insulin
administration – the only other option towards a path to insulin independence is donor islets/whole organ
transplant, a limited resource, that replaces the cohort of cells that are lost in patients due to an autoimmune
attack. The success of these transplants is highly variable, with several patients requiring a second or
sometimes a third infusion of donor cells. Failure of allogeneic cell/tissue transplant often results from immune
activation within the host, and strong systemic immunosuppression is necessary for successful engraftment of
the transplant. Numerous approaches have been undertaken to alleviate the need for systemic
immunosuppression – those focused on manipulating the graft have genetically removed the expression of cell
surface proteins that, when mis-matched, lead to activation of the adaptive and innate immune systems. Such
cells are potentially invisible to the immune system and pose the grave problem of serving as potential
reservoirs of infection. If we had a method of identifying when a graft was experiencing inflammatory stress, we
could design acute anti-inflammatory therapies to protect the graft from the assault – prolonging the time it
takes for the graft to get accustomed to the niche and begin functioning. More recently, stem cells have
emerged as a limitless resource of cells as a surrogate to donor islets, and early clinical attempts are currently
underway. Replacement with stem cell derivatives circumvents the roadblock of limited transplant material –
they are still faced with immune activation due to an allo-response after transplantation.
Our goal is to address these challenges using state-of-the-art technologies we have pioneered. Combining the
potential of stem cell therapy with an intracellular biosensing system that provides real time feedback in
response to the transplantation niche, we will leapfrog allogeneic cell transplantation into the future – such a
detection system can measure viability of grafts that can be predictive of successful engraftment and help
define interventions to protect cells against inflammatory stress soon after transplantation. We have
engineered nanoprobes that bind and respond to changes in miRNA levels and serve as intracellular sensors
for cell health. Our nanoprobes are specific, sensitive, and can be detected in vivo in animal models.
Here, we test our lead inflammation-sensitive biosensor in stem cell-derived insulin producing organoids – this
combination can provide unique spectral read outs, in vitro and in small animal models, that result from a
specific inflammatory response triggered in the cells, de-risking our final cell therapy product that will become
part of a functional cure for patients living with type 1 diabetes.
项目总结/摘要
1型糖尿病患者通过每日外源性胰岛素调节血糖
给药-通往胰岛素独立性途径的唯一其他选择是供体胰岛/整个器官
移植是一种有限的资源,它取代了由于自身免疫性疾病而在患者中丢失的细胞群。
攻击这些移植的成功是高度可变的,有几个病人需要第二次或第三次移植。
有时是第三次输注供体细胞同种异体细胞/组织移植的失败通常是由于免疫缺陷引起的。
在宿主内激活,并且强的全身性免疫抑制对于成功植入
移植手术已经采取了许多方法来减轻系统性的
免疫抑制-那些专注于操纵移植物的人已经从基因上去除了细胞的表达,
表面蛋白质,当错配时,导致适应性和先天免疫系统的激活。等
细胞是潜在的不可见的免疫系统,并提出了严重的问题,作为潜在的
传染源如果我们有一种方法来识别移植物何时经历炎症应激,
可以设计急性抗炎治疗,以保护移植物免受攻击-延长时间,
需要移植物适应利基并开始发挥作用。最近,干细胞已经
作为供体胰岛的替代物,作为无限的细胞资源出现,目前还没有早期的临床尝试。
正在进行中用干细胞衍生物替代绕过了有限移植材料的障碍-
它们在移植后仍然面临由于同种异体反应引起的免疫激活。
我们的目标是使用我们开创的最先进技术来应对这些挑战。结合
利用细胞内生物传感系统提供真实的时间反馈,
响应移植生态位,我们将跨越同种异体细胞移植到未来-这样一个
检测系统可以测量移植物的活力,这可以预测成功的植入,
定义干预措施,以保护细胞免受移植后不久的炎症应激。我们有
工程纳米探针,结合并响应miRNA水平的变化,并作为细胞内传感器
for cell细胞health健康.我们的纳米探针具有特异性、灵敏性,并且可以在动物模型中进行体内检测。
在这里,我们在干细胞衍生的胰岛素产生类器官中测试了我们的铅炎症敏感生物传感器-这
组合可以提供独特的光谱读数,在体外和小动物模型中,这是由于
在细胞中引发特定的炎症反应,降低我们最终的细胞治疗产品的风险,
1型糖尿病患者的部分功能性治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Catherine Digovich其他文献
Catherine Digovich的其他文献
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{{ truncateString('Catherine Digovich', 18)}}的其他基金
Real-time intracellular monitoring of microRNAs in human stem cell-derived insulin producing organoids
实时细胞内监测人类干细胞衍生的胰岛素产生类器官中的 microRNA
- 批准号:
10296294 - 财政年份:2021
- 资助金额:
$ 87万 - 项目类别:
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