Microelectrode oxygenation control of tumor necrosis

微电极氧合控制肿瘤坏死

• 批准号: 6969827
• 负责人: NEIL S. FORBES
• 金额: $ 19.3万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-22 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6969827
• 关键词: biomedical equipment development; biotechnology; cell death; cell line; cellular pathology; fluorescence microscopy; growth inhibitors; hypoxia inducible factor 1; necrosis; neoplasm /cancer therapy; neoplastic process; oxygen microelectrode; oxygen tension; oxygen therapy; oxygen transport; receptor expression

DESCRIPTION (provided by applicant): Heterogeneous delivery of oxygen to tissues plays a crucial role in many biological processes and the treatment of many diseases. This proposal describes the use of a novel oxygen microelectrode device to measure the effect of localized oxygen delivery on tumor necrosis. The specific goals are to: 1) develop an oxygen microgradient chip that allows measurement and control of the oxygen environment in a tissue with microscale spatio-temporal resolution; 2) precisely deliver oxygen to tumor tissue, measure individual cell death, and determine the extent that poor oxygenation causes tumor necrosis; and 3) demonstrate that a HIF1-alpha response is critical for cell survival in hypoxic tumor tissue. Tumor hypoxia and necrosis are both caused by poor oxygen supply and are both correlated with poor patient prognosis. Hypoxia inducible factor1-alpha (HIF1-alpha) is a promising therapeutic target because it promotes cell survival in hypoxic conditions, which may lead to tumor growth. No technology currently exists that allows control of the oxygen microenvironment of tissues with cellular resolution. The proposed device will generate stable microgradient gas profiles that are responsive to transient experimental conditions. This device will be useful with a wide range of tissues and applications including tissue engineering and stem cell differentiation. In this proposal, oxygen will be delivered to HIF1-a-containing and null in vitro tumors while preserving other concentration gradients (glucose, acidic waste products, etc.). By measuring the extent of cell death, the effect of oxygen gradients on cell survival will be independently discerned. Many promising therapeutics are being designed to target the unique microenvironments of tumors. Here, precisely controlled experiments will evaluate the therapeutic potential of targeting both hypoxia and HIF1-alpha. In summary, microelectrodes will be used to deliver oxygen to three-dimensional tumor tissue to measure the effect of oxygen on cell survival and HIF1-alpha expression.

描述（由申请人提供）：氧向组织的不均匀输送在许多生物过程和许多疾病的治疗中起着至关重要的作用。本提案描述了一种新型氧微电极装置的使用，以测量局部氧气输送对肿瘤坏死的影响。具体目标是：1)开发一种氧气微梯度芯片，允许以微尺度时空分辨率测量和控制组织中的氧气环境；2)精确向肿瘤组织输送氧气，测量个体细胞死亡情况，确定缺氧导致肿瘤坏死的程度；3)证明hif1 - α反应对缺氧肿瘤组织中的细胞存活至关重要。肿瘤缺氧和坏死都是由供氧不足引起的，都与患者预后不良有关。缺氧诱导因子- α (hif1 - α)是一个很有前景的治疗靶点，因为它可以促进缺氧条件下的细胞存活，从而导致肿瘤生长。目前还没有技术可以用细胞分辨率来控制组织的氧微环境。所提出的装置将产生稳定的微梯度气体剖面，响应瞬态实验条件。该装置将用于广泛的组织和应用，包括组织工程和干细胞分化。在本方案中，氧气将被输送到含hif1 -a和无hif1 -a的体外肿瘤中，同时保留其他浓度梯度（葡萄糖、酸性废物等）。通过测量细胞死亡的程度，氧梯度对细胞存活的影响将被独立识别。许多有希望的治疗方法都是针对肿瘤独特的微环境而设计的。在这里，精确控制的实验将评估针对缺氧和hif1 - α的治疗潜力。综上所述，微电极将用于向三维肿瘤组织输送氧气，以测量氧气对细胞存活和hif1 - α表达的影响。