Pluripotent Stem Cell Vascular Therapies for Ischemic Retinopathies
缺血性视网膜病的多能干细胞血管疗法
基本信息
- 批准号:8892184
- 负责人:
- 金额:$ 35.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-01 至 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAngioblastAnimal ModelAutologousBackBlindnessBloodBlood CellsBlood VesselsBlood capillariesBlood specimenCXCR4 geneCell LineCell TherapyCessation of lifeCharacteristicsChronicClinicalDerivation procedureDevelopmentDiabetes MellitusDiabetic RetinopathyDiseaseEmbryoEndothelial CellsEngraftmentEnvironmentEpigenetic ProcessEyeFetal DevelopmentFibroblastsFutureGenerationsGoalsHealthHematopoieticHomingHumanHypoxiaInjuryIschemiaIslet CellLegal patentLifeMCAM geneMesenchymalMesodermMethodsModelingMolecularMusMyelogenousNatural regenerationNeural RetinaNeuronsNude RatsPECAM1 genePatientsPericytesPhotoreceptorsPluripotent Stem CellsPrincipal InvestigatorReperfusion InjuryReperfusion TherapyReportingResearch PersonnelRetinaRetinalRetinal DiseasesRetinal PhotoreceptorsRodentSignal TransductionSinusSourceStagingStem cell transplantStem cellsSystemTechnologyTestingTherapeuticTissuesTransplant RecipientsTransplantationVascular Endothelial CellVascular EndotheliumVascular blood supplyVisionbasecapillarycell typediabeticimprovedinduced pluripotent stem cellnovelpre-clinicalprogenitorprogramsregenerativerelating to nervous systemrepairedretinal damageretinal neuronself-renewalvein occlusion
项目摘要
DESCRIPTION (provided by applicant): Branch vein occlusion (BVO) and diabetic retinopathy (DR) are the major causes of new onset blindness in the US. Both disorders result in acellular capillaries due to ischemic death of retinal vascular endothelial cells (ECs) and contractile pericytes. If acellular retinal capillaries could be repopulated with autologous vascular/pericytic
progenitors, ischemia could be relieved and end stage blindness reversed in these diseases. One such approach is to transplant patient-specific embryonic vascular progenitors (VP) with prolific vascular and mesenchymal-pericytic potential. Such progenitors could be generated from human induced pluripotent stem cells (hiPSC) and transplanted directly into the eye. This approach could be combined with parallel differentiation from the same hiPSC line to replace ischemic degenerated retinal neural tissue along with their requisite vascular niche. To date, no one has evaluated hiPSC-derived embryonic VP for capacity to engraft and rescue degenerated vasculature in the ischemic retina. In this proposal, we will test the potential of hiPSC-derived embryonic VP to efficiently differentiate to ECs and pericytes following engraftment into damaged ischemic retina. We will use animal models that mimic human BVO [i.e., ischemia/reperfusion (I/R) injury] or DR (induced in athymic rats) for testing the potential of hiPSC-derived VP to form patent blood vessels and rescue ischemic retina. We will inject hiPSC-derived CXCR4+ VP expressing endothelial (CD31+) and pericytic- mesenchymal (CD146+) markers directly into the vitreous space (or IV orbital sinus) of immunodeficient NOD/scid mouse eyes that have been experimentally degenerated by I/R injury or diabetes. We will then test the ability of these progenitors for their ability to repopulate and regenerate viabe capillaries, rescue neural retina, and improve visual function. We will also determine the retinal micro-environmental injury and hypoxia-related signals that regulate homing and engraftment of CXCR4+ embryonic VPs to acellular retinal capillaries. We hypothesize that efficient generation of vascular progenitors from nonviral myeloid-iPSC will ultimately have superior clinical utility fr the treatment of ischemic ocular diseases. If successful, our approach would allow facile generation of autologous, multipotent, and clinically useful vascular-forming precursors reprogrammed from a patient's own blood cells to be used in clinical therapies for BVO and DR.
描述(由申请人提供):分支静脉阻塞(BVO)和糖尿病视网膜病变(DR)是美国新发失明的主要原因。这两种疾病都会因视网膜血管内皮细胞(EC)和收缩周细胞的缺血性死亡而导致毛细血管无细胞。如果非细胞视网膜毛细血管可以用自体血管/周细胞重新填充
在这些疾病中,祖细胞、缺血可以得到缓解,末期失明也可以得到逆转。其中一种方法是移植具有丰富血管和间充质周细胞潜力的患者特异性胚胎血管祖细胞(VP)。这种祖细胞可以从人类诱导多能干细胞(hiPSC)中产生并直接移植到眼睛中。这种方法可以与同一 hiPSC 系的平行分化相结合,以取代缺血性退化的视网膜神经组织及其必需的血管生态位。迄今为止,尚未有人评估 hiPSC 衍生的胚胎 VP 移植和挽救缺血性视网膜退化脉管系统的能力。在本提案中,我们将测试 hiPSC 衍生的胚胎 VP 在植入受损缺血性视网膜后有效分化为 EC 和周细胞的潜力。我们将使用模拟人类 BVO [即缺血/再灌注 (I/R) 损伤] 或 DR(在无胸腺大鼠中诱导)的动物模型来测试 hiPSC 衍生的 VP 形成开放血管和挽救缺血性视网膜的潜力。我们将表达内皮细胞 (CD31+) 和周细胞间充质 (CD146+) 标记物的 hiPSC 衍生的 CXCR4+ VP 直接注射到免疫缺陷 NOD/scid 小鼠眼睛的玻璃体空间(或 IV 眼眶窦)中,这些小鼠眼睛已在实验中因 I/R 损伤而退化,或糖尿病。然后,我们将测试这些祖细胞重新填充和再生毛细血管、拯救神经视网膜和改善视觉功能的能力。我们还将确定视网膜微环境损伤和缺氧相关信号,这些信号调节 CXCR4+ 胚胎 VP 向无细胞视网膜毛细血管的归巢和植入。我们假设,从非病毒性骨髓-iPSC 中有效生成血管祖细胞最终将在治疗缺血性眼病方面具有卓越的临床实用性。如果成功,我们的方法将能够轻松地从患者自身的血细胞中生成自体、多能且临床有用的血管形成前体,用于 BVO 和 DR 的临床治疗。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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ELIAS T. ZAMBIDIS其他文献
ELIAS T. ZAMBIDIS的其他文献
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{{ truncateString('ELIAS T. ZAMBIDIS', 18)}}的其他基金
Embryonic vascular stem-progenitors for treatment of ischemic retinopathies
用于治疗缺血性视网膜病的胚胎血管干祖细胞
- 批准号:
10334409 - 财政年份:2021
- 资助金额:
$ 35.72万 - 项目类别:
Embryonic vascular stem-progenitors for treatment of ischemic retinopathies
用于治疗缺血性视网膜病的胚胎血管干祖细胞
- 批准号:
10557078 - 财政年份:2021
- 资助金额:
$ 35.72万 - 项目类别:
Functional Vascular Progenitors from Naive Human iPSC
来自原始人类 iPSC 的功能性血管祖细胞
- 批准号:
9059743 - 财政年份:2015
- 资助金额:
$ 35.72万 - 项目类别:
Functional Vascular Progenitors from Naive Human iPSC
来自原始人类 iPSC 的功能性血管祖细胞
- 批准号:
9220844 - 财政年份:2015
- 资助金额:
$ 35.72万 - 项目类别:
Functional Vascular Progenitors from Naive Human iPSC
来自原始人类 iPSC 的功能性血管祖细胞
- 批准号:
8797928 - 财政年份:2015
- 资助金额:
$ 35.72万 - 项目类别:
Pluripotent Stem Cell Vascular Therapies for Ischemic Retinopathies
缺血性视网膜病的多能干细胞血管疗法
- 批准号:
8758998 - 财政年份:2014
- 资助金额:
$ 35.72万 - 项目类别:
Pluripotent Stem Cell Vascular Therapies for Ischemic Retinopathies
缺血性视网膜病的多能干细胞血管疗法
- 批准号:
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- 资助金额:
$ 35.72万 - 项目类别:
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8758998 - 财政年份:2014
- 资助金额:
$ 35.72万 - 项目类别:
Pluripotent Stem Cell Vascular Therapies for Ischemic Retinopathies
缺血性视网膜病的多能干细胞血管疗法
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