Microelectrode oxygenation control of tumor necrosis

描述（由申请人提供）：氧气向组织的异质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。 该提案描述了使用一种新型的氧微电极装置来测量局部氧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）精确地将氧气输送到肿瘤组织，测量个体细胞死亡，并确定缺氧导致肿瘤坏死的程度; 3）证明HIF 1-α反应对于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氧气供应不足引起的，并且都与患者预后不良相关。 缺氧诱导因子1-α（HIF 1-α）是一个有前途的治疗靶点，因为它促进细胞在缺氧条件下的存活，这可能导致肿瘤生长。 目前不存在允许以细胞分辨率控制组织的氧微环境的技术。 所提出的装置将产生稳定的微梯度气体分布，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。 在该提议中，氧气将被递送至含HIF 1-a的体外肿瘤和空肿瘤，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，将独立地辨别氧梯度对细胞存活的影响。 许多有前途的治疗方法正在被设计成靶向肿瘤的独特微环境。 在这里，精确控制的实验将评估靶向缺氧和HIF 1-α的治疗潜力。 总之，微电极将用于将氧气输送到三维肿瘤组织，以测量氧气对细胞存活和HIF 1-α表达的影响。

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.