BIOMATERIALS FOR STEM CELL-DERIVED BETA CELL TRANSPLANTATION
用于干细胞衍生的 β 细胞移植的生物材料
基本信息
- 批准号:10306891
- 负责人:
- 金额:$ 40.76万
- 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:2021-09-17 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdhesivesAdultAdverse effectsAffectAutoimmuneAutoimmune DiseasesBeta CellBiochemicalBiocompatible MaterialsBiophysicsBlood GlucoseBody WeightC-PeptideCadaverCell MaturationCell TransplantationCell physiologyCellsCharacteristicsChildChronicClinicalClinical TrialsCuesDevelopmentDiagnosisEncapsulatedEngineeringEngraftmentEvaluationExtrahepaticFastingFatty acid glycerol estersFormulationFoundationsFutureGelGlucoseGlucose tolerance testGreater omentumHealth Care CostsHematopoietic stem cellsHomologous TransplantationHumanHydrogelsHypoglycemiaImmuneImmune mediated destructionImmune systemImmunocompetentImmunocompromised HostImmunologyImmunosuppressionImmunosuppressive AgentsIn VitroInsulinInsulin-Dependent Diabetes MellitusIslets of Langerhans TransplantationLigandsLymphocyteMaleimidesModelingMonitorMusPatientsPeptide HydrolasesPeripheral Blood Mononuclear CellPermeabilityPhase III Clinical TrialsPopulationSignal TransductionSiteSourceStructure of beta Cell of isletTechnologyTranslationsTransplantationVascularizationWorkarmbasecell replacement therapyclinical translationclinically translatablediabeticethylene glycoleuglycemiaglycemic controlhuman embryonic stem cellhuman embryonic stem cell transplantationhuman pluripotent stem cellhuman stem cellshumanized mouseimmunoregulationimprovedinduced pluripotent stem cellinnovationinsulin secretionisletmechanical propertiesmouse modelnonhuman primatenovelnovel strategiespreventstem cell biologystem cells
项目摘要
PROJECT SUMMARY
Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing β-cells of the pancreas are
destroyed. T1D affects 3 million children and adults in the US with healthcare costs exceeding $15 billion.
Standard therapy with exogenous insulin is burdensome, associated with a significant danger of hypoglycemia,
and only partially efficacious in preventing long-term complications. Transplantation of allogeneic islets from
cadaveric donors in conjunction with chronic immunosuppression has been recently shown to be effective in
restoring euglycemia in clinical trials. However, the long-term future of cell replacement therapy for T1D requires
a reliable and replenishable β-cell source and elimination of the need for chronic immunosuppression. β-cells
derived from human pluripotent stem cells (hPSC) represent a transformative, unlimited source of insulin-
producing cells for the treatment of T1D. However, the resulting cell population is heterogeneous and the
development of mature insulin-producing cells is inconsistent. Furthermore, significant barriers related to long-
term engraftment and function without chronic immunosuppression prevent the application of these promising
cells. The objective of this project is to engineer biomaterials that (i) promote maturation and function of human
pluripotent stem cell (hPSC)-derived β-cells and (ii) protect them from rejection by the immune system without
the need for chronic immunosuppression. It is hypothesized that synthetic hydrogels with optimal biophysical
and biochemical characteristics will provide a material platform that directs hPSC-derived β-cell maturation,
engraftment and function without chronic immunosuppression. Aim 1: Engineer synthetic hydrogel formulations
that promote survival, maturation, and function of immature β-cells. Aim 2: Evaluate engineered hydrogels as
delivery carriers for β-cell transplantation in diabetic, immunocompromised mice. Aim 3: Engineer
immunomodulatory hydrogels to promote hPSC-derived β-cell immune-acceptance and function in diabetic,
immunocompetent humanized mice without chronic immunosuppression. This highly innovative novel strategy
is fundamentally different from ongoing work in the field in terms of (i) engineering materials that provide
microenvironmental cues to promote maturation of β-cells and local immune acceptance to eliminate the need
of chronic systemic immunosuppressive drugs, (ii) transplantation into a clinically-translatable extrahepatic site
with high vascularization and engraftment potential, and (iii) evaluation in humanized mice to provide proof-of-
efficacy as a prelude to clinical translation. This project will provide a significant foundation for translation of this
promising human cell source and will establish innovative materials that promote survival, engraftment, and
function of human stem cell-derived β-cells in immunocompetent diabetic hosts.
项目总结
1型糖尿病(T1D)是一种自身免疫性疾病,胰腺中产生胰岛素的β细胞
被毁了。T1D影响了美国300万儿童和成人,医疗成本超过150亿美元。
外源性胰岛素的标准治疗是繁重的,与低血糖的重大危险有关,
在预防长期并发症方面只有部分有效。同种异体胰岛移植的实验研究
身体供体联合慢性免疫抑制最近被证明是有效的
在临床试验中恢复正常血糖。然而,T1D细胞替代疗法的长期未来需要
一种可靠和可补充的β细胞来源,消除了慢性免疫抑制的需要。β细胞
来源于人类多能干细胞(HPSC)的干细胞代表着一种变革性的、无限的胰岛素来源--
产生治疗T1D的细胞。然而,由此产生的细胞群体是异质的,并且
成熟的胰岛素分泌细胞的发育并不一致。此外,与长期-
在没有慢性免疫抑制的情况下,术语植入和功能阻止了这些有希望的应用
细胞。这个项目的目标是设计生物材料,以(I)促进人类的成熟和功能
多能干细胞(HPSC)来源的β细胞和(Ii)保护它们免受免疫系统的排斥,而不是
慢性免疫抑制的必要性。假设合成水凝胶具有最佳的生物物理性能
生化特性将提供指导hPSC来源的β细胞成熟的物质平台,
植入和功能不受慢性免疫抑制的影响。目标1:设计合成水凝胶配方
促进未成熟β细胞的存活、成熟和功能。目标2:评估工程水凝胶为
用于糖尿病、免疫受损小鼠β细胞移植的递送载体。目标3:工程师
免疫调节性水凝胶促进糖尿病患者hPSC来源的β细胞免疫接受和功能
无慢性免疫抑制的免疫活性人源化小鼠。这一极具创新性的新战略
在以下方面从根本上不同于该领域正在进行的工作:(I)提供
促进β细胞成熟和局部免疫接受的微环境线索消除了这种需要
慢性全身性免疫抑制药物,(Ii)移植到临床可翻译的肝外部位
具有很高的血管形成和植入潜力,以及(Iii)在人源化小鼠中的评估提供了证据
疗效作为临床翻译的前奏。该项目将为翻译这篇文章提供一个重要的基础
有希望的人类细胞来源,并将建立创新的材料,促进生存,植入和
人干细胞来源的β细胞在免疫活性糖尿病宿主中的功能。
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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Andres J Garcia其他文献
Andres J Garcia的其他文献
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{{ truncateString('Andres J Garcia', 18)}}的其他基金
Hydrogels for human beta cell survival, function and evasion of immune rejection
用于人类β细胞存活、功能和逃避免疫排斥的水凝胶
- 批准号:
10512947 - 财政年份:2022
- 资助金额:
$ 40.76万 - 项目类别:
Hydrogels for human beta cell survival, function and evasion of immune rejection
用于人类β细胞存活、功能和逃避免疫排斥的水凝胶
- 批准号:
10705265 - 财政年份:2022
- 资助金额:
$ 40.76万 - 项目类别:
Hydrogels for human beta cell survival, function and evasion of immune rejection
用于人类β细胞存活、功能和逃避免疫排斥的水凝胶
- 批准号:
10865870 - 财政年份:2022
- 资助金额:
$ 40.76万 - 项目类别:
BIOMATERIALS FOR STEM CELL DERIVED BETA CELL TRANSPLANTATION
用于干细胞衍生的 β 细胞移植的生物材料
- 批准号:
10517827 - 财政年份:2021
- 资助金额:
$ 40.76万 - 项目类别:
BIOMATERIALS FOR STEM CELL-DERIVED BETA CELL TRANSPLANTATION
用于干细胞衍生的 β 细胞移植的生物材料
- 批准号:
10684716 - 财政年份:2021
- 资助金额:
$ 40.76万 - 项目类别:
BIOMATERIALS FOR STEM CELL-DERIVED BETA CELL TRANSPLANTATION
用于干细胞衍生的 β 细胞移植的生物材料
- 批准号:
10557968 - 财政年份:2021
- 资助金额:
$ 40.76万 - 项目类别:
BIOMATERIALS FOR STEM CELL-DERIVED BETA CELL TRANSPLANTATION
用于干细胞衍生的 β 细胞移植的生物材料
- 批准号:
10905940 - 财政年份:2021
- 资助金额:
$ 40.76万 - 项目类别:
Targeted delivery of immunomodulatory biologics for induction of immune privilege to allogeneic pancreatic islet grafts
靶向递送免疫调节生物制剂以诱导同种异体胰岛移植物的免疫特权
- 批准号:
10227259 - 财政年份:2020
- 资助金额:
$ 40.76万 - 项目类别:
Hydrogels for delivery of muscle stem cells to diaphragm
用于将肌肉干细胞递送至隔膜的水凝胶
- 批准号:
10281444 - 财政年份:2020
- 资助金额:
$ 40.76万 - 项目类别:
Targeted delivery of immunomodulatory biologics for induction of immune privilege to allogeneic pancreatic islet grafts
靶向递送免疫调节生物制剂以诱导同种异体胰岛移植物的免疫特权
- 批准号:
10163042 - 财政年份:2020
- 资助金额:
$ 40.76万 - 项目类别:
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