CNS Radiation Injury: Regeneration via Human ES Cells

中枢神经系统辐射损伤：通过人类胚胎干细胞再生

• 批准号: 7418693
• 负责人: VIVIANE TABAR
• 金额: $ 32.38万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-08 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418693
• 关键词: Address; Adult; Adverse effects; Affect; Behavior assessment; Behavioral; Brain; Brain Neoplasms; Cancer Patient; Cell Count; Cells; Childhood; Clinical; Cognitive; Complex; Corpus Callosum; Cranial Irradiation; Data; Demyelinations; Derivation procedure; Deterioration; Embryo; Goals; Human; In complete remission; Lead; Learning; Leukemia in Remission; Literature; Lymphoma; Malignant Neoplasms; Memory; Modeling; Natural regeneration; Oligodendroglia; Outcome; Pathogenesis; Patients; Pilot Projects; Placement; Population; Productivity; Protocols documentation; Quality of life; Radiation; Radiation Injuries; Radiation induced damage; Rattus; Role; Slice; Source; Stem cells; Time; Tissues; Transplantation; United States National Institutes of Health; age group; base; cerebral atrophy; cognitive function; exhaustion; human embryonic stem cell; in vivo; irradiation; migration; myelination; progenitor; radiation effect; repaired; restoration; stem; young adult; Address; Adult; Adverse effects; Affect; Behavior assessment; Behavioral; Brain; Brain Neoplasms; Cancer Patient; Cell Count; Cells; Childhood; Clinical; Cognitive; Complex; Corpus Callosum; Cranial Irradiation; Data; Demyelinations; Derivation procedure; Deterioration; Embryo; Goals; Human; In complete remission; Lead; Learning; Leukemia in Remission; Literature; Lymphoma; Malignant Neoplasms; Memory; Modeling; Natural regeneration; Oligodendroglia; Outcome; Pathogenesis; Patients; Pilot Projects; Placement; Population; Productivity; Protocols documentation; Quality of life; Radiation; Radiation Injuries; Radiation induced damage; Rattus; Role; Slice; Source; Stem cells; Time; Tissues; Transplantation; United States National Institutes of Health; age group; base; cerebral atrophy; cognitive function; exhaustion; human embryonic stem cell; in vivo; irradiation; migration; myelination; progenitor; radiation effect; repaired; restoration; stem; young adult

DESCRIPTION (provided by applicant): The goal of this project is to investigate the potential of human embryonic stem (hES) cell derived oligoprogenitors as restorative therapy for radiation-induced damage in the brain at the structural and functional levels. The project is based on a substantial body of preliminary data including high yield derivation of oligoprogenitors from human ES cells (NIH approved lines WA-01 and WA-09), survival and differentiation of hES derived progenitors in rat brains, and a quantitative study of the deleterious and irreversible effects of radiation to the adult rat brain. Radiation damage to the brain is a significant clinical problem in cancer management, affecting patients with primary as well as metastatic brain tumors. The effects of radiation to the brain generally occur late (>6-12 months after exposure) and lead to irreversible deterioration in cognitive function. The pathogenesis of late radiation damage is complex, but the pathological outcome is characterized by demyelination and subsequent cerebral atrophy. The radiation model remains essentially unexplored as a possible target for cell replacement despite significant literature pertaining to histopathological changes and the terrible toll on quality of life of the cancer patient. We demonstrate that irradiation results in exhaustion of the cycling oligodendrocyte progenitor pool, with subsequent inability of the brain to replace mature myelinating cells. We have recently developed protocols for the highly efficient differentiation of hES cells into oligoprogenitors. Here we propose to address their potential for repairing radiation damage to the CNS. We will purify the oligoprogenitor populations and perform pilot studies in irradiated rats in an effort to optimize cell numbers, migration, survival and favorable timing of graft placement post irradiation. Once these parameters are elucidated, we will proceed with long term oligoprogenitor or sham grafts in irradiated rats and perform careful behavioral assessments of learning, memory and cognitive tasks, as well electrical studies on brain slices to study conduction across the corpus callosum. We hope to demonstrate the role of hES derived oligoprogenitors in cytoarchitectural restoration of myelination and tissue and behavioral function post radiation. This proposal will use exclusively NIH approved hES lines: WA-01 and WA-09.

描述（由申请人提供）：该项目的目的是研究人类胚胎茎（HES）细胞衍生的寡聚生构的潜力，作为在结构和功能水平下辐射诱导大脑损伤的恢复性疗法。 该项目基于大量的初步数据，包括从人ES细胞（NIH认可的WA-01和WA-09），大鼠大脑中hes衍生的祖细胞的生存和分化以及对辐射对成年大鼠辐射的无可逆性和不可逆影响的定量研究的少产源性的高产量推导。大脑的辐射损害是癌症管理中的一个重大临床问题，影响了原发性和转移性脑肿瘤患者。 辐射对大脑的影响通常发生晚期（暴露后6-12个月> 6-12个月），并导致认知功能不可逆地恶化。 晚期辐射损伤的发病机理是复杂的，但是病理结局的特征是脱髓鞘和随后的大脑萎缩。尽管与组织病理学变化有关，并且对癌症患者的生活质量造成了严重的损失，但基本上仍未开发辐射模型作为细胞替代的可能目标。我们证明了辐照导致循环少突胶质细胞祖细胞库的精疲力尽，随后大脑无法替代成熟的髓鞘细胞。我们最近开发了将HES细胞高效分化为寡聚生物基因生成剂的方案。在这里，我们建议解决它们修复CNS辐射损害的潜力。我们将净化少产元素种群，并在辐照大鼠中进行试验研究，以优化辐射后移植放置的细胞数量，迁移，生存和有利的时机。一旦阐明了这些参数，我们将在辐照大鼠中进行长期的寡聚生子或假手术，并对学习，记忆和认知任务进行仔细的行为评估，以及对脑切片的电气研究，以研究callosum callosum callosum的传导。我们希望证明HES衍生的寡聚生物基因在辐射后的髓鞘和组织的细胞结构恢复中的作用。该提案将仅使用NIH批准的HES行：WA-01和WA-09。