Radiation Damage Repair in the Brain via Human ES cells

通过人类 ES 细胞修复大脑辐射损伤

• 批准号: 6602653
• 负责人: VIVIANE TABAR
• 金额: $ 18.54万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6602653
• 关键词: brain injury; cell population study; developmental neurobiology; human embryonic stem cell line; laboratory rat; myelination; nervous system regeneration; nonhuman therapy evaluation; oligodendroglia; radiation recovery; stem cell transplantation; therapy adverse effect

DESCRIPTION (provided by applicant): Brain irradiation is a powerful tool in the treatment of cancers including primary and metastatic many tumors, and even leukemias and lymphomas. However its use is restricted by the poor tolerance of the nervous tissue and the development of serious side effects among long-term survivors. These include a decline in IQ and cognitive function. This phenomenon is very frequent and irreversible. Its pathogenesis is not fully elucidated but it involves extensive demyelination occurring in a delayed fashion (months to years). Based on preliminary data obtained in the rat, we hypothesize that radiation exhausts the pool of dividing oligodendrocyte progenitors (OPC) and therefore the brain's ability to replace the myelinating cells. We have developed significant experience in the neural differentiation of human ES (hES) cells and we propose the transplantation of hES-derived neural precursors as an effective strategy for repair of radiation-induced brain damage. We will study the temporal and topographic pattern of cell loss following whole brain irradiation in the rat at five timepoints over the course of one year. The rats will receive BrdU prior to sacrifice and the brains will be processed for BrdU, NG2 (an OPC marker) and other neural markers. We will then graft irradiated rats with two different populations of neural precursors obtained from hES cells: a multipotential neural stem cell-like population, and an oligodendroglial progenitor population. In our preliminary data we have successfully derived such cells from hES cells and established stable eGFP-expressing hES cells via lentiviral gene transfer for reliable in vitro and in vivo identification. Grafted animals will be examined at 6 weeks after transplantation to assess cell survival, migration, and ability to replace the OPC niche, and at 6-8 months after transplantation to evaluate the ability of hES cells to contribute to remyelination of the injured brain. This work addresses a therapeutically important problem in brain cancer treatment and will provide a wealth of information on the behavior of grafted human ES cells within the context of an injured brain. If successful, we plan to initiate future studies addressing the functional impact of hES-derived neural precursor grafts on radiation-induced cognitive decline. This grant will only use the INIH-approved cell line: HI. NIH code WA01.

描述（由申请人提供）：脑照射是治疗癌症的有力工具，包括原发性和转移性许多肿瘤，甚至白血病和淋巴瘤。然而，它的使用受到神经组织耐受性差和长期存活者中严重副作用的发展的限制。这些包括智商和认知功能的下降。这种现象是非常频繁和不可逆转的。其发病机制尚未完全阐明，但涉及以延迟方式（数月至数年）发生的广泛脱髓鞘。基于在大鼠中获得的初步数据，我们假设辐射耗尽了分裂的少突胶质细胞祖细胞（OPC）的池，因此大脑取代髓鞘形成细胞的能力。我们已经开发了显着的经验，在神经分化的人ES（hES）细胞，我们提出了移植的hES衍生的神经前体作为一种有效的策略，用于修复辐射引起的脑损伤。 我们将在一年的时间内，在五个时间点研究大鼠全脑照射后细胞丢失的时间和地形模式。大鼠在处死前接受BrdU，并处理大脑中的BrdU、NG 2（OPC标记物）和其他神经标记物。然后，我们将移植辐射大鼠与两个不同的群体的神经前体细胞获得的人胚胎干细胞：多能神经干细胞样人口，和少突胶质细胞祖细胞人口。在我们的初步数据中，我们已经成功地从hES细胞中获得了这样的细胞，并通过慢病毒基因转移建立了稳定的表达eGFP的hES细胞，用于可靠的体外和体内鉴定。在移植后6周检查移植动物以评估细胞存活、迁移和替换OPC小生境的能力，并在移植后6-8个月检查移植动物以评估hES细胞促进受损脑髓鞘再生的能力。这项工作解决了脑癌治疗中一个重要的治疗问题，并将提供大量关于移植的人类ES细胞在受损大脑中的行为的信息。如果成功，我们计划启动未来的研究，解决hES衍生的神经前体移植物对辐射诱导的认知能力下降的功能影响。 这项资助将只使用INIH批准的细胞系：HI。NIH代码WA 01。