Analysis of brain/heart pathogenesis based on mitochondiral function and its application to nuclear medicine.

基于线粒体功能的脑/心脏发病机制分析及其在核医学中的应用。

• 批准号: 11670882
• 负责人: FUJIBAYASHI Yasuhisa
• 金额: $ 1.92万
• 依托单位: Fukui Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670882/
• 关键词: electron transport; hypoxia; ischemia; nuclear medicine; radiopharmaceutical; copper; ミトコンドリア; 脳障害; エネルギー代謝; ラット; マウス; 脳組織切片

Mitochondiria is an important intracellular organism for aerobic energy production, having its own gene and expression system. Normally, mitochondria and other intracellular origanisms are closely linkaged, but failture in this linkage is said to be a cause of oxidative stress such as ischemia-reperfison injury, especially in brain or heart. Understanding the process of failure in this linkage will bring a new sight of pathogenesis of ishcemic disease in brain/heart and allow us to develop new diagnostic method in nuclear medicine. In this research, new radioactive copper labeled radiopharmacetucals, have been developmed and electron transport failure could be visualized in diseased animal models as well as human patients. Radioiodinated Fatty acid derivative has been evaluated as a marker of myocardial energy failure, and its usefulness could be clarified. Dynamic analysis of brain uptake of fluorine-18-labeled fluorodeoxyglucose (FDG) in ischemic/hypoxic brain slices brought us an difference in contribution of radical formation and glutamate release to the reversibility of damage in the brain. This methodology allows us to clarify the drug effect on neuronal damage under strictly controlled conditions.As an additional research, hypoxia tolerance of tumors can be also studied in comparison with hypoxia of non-tumor tissues. Based on the results of this work, development of therapeutic radiopharmaceutical for hypoxic tumor selective radiotherapy could be performed successfully.

线粒体是一种重要的胞内有氧能量生物，具有自己的基因和表达系统。正常情况下，线粒体和其他细胞内起源是紧密相连的，但这种联系的失败被认为是氧化应激的原因，如缺血再灌注损伤，特别是在大脑或心脏。了解这种联系的失败过程将为脑/心脏缺血性疾病的发病机制带来新的视角，并使我们能够发展新的核医学诊断方法。在这项研究中，已经开发了新的放射性铜标记的放射性药物，并且可以在疾病动物模型和人类患者中观察到电子传递失败。放射性碘化脂肪酸衍生物已被评价为心肌能量衰竭的标志物，其有用性有待阐明。对脑缺血/缺氧脑片摄取氟-18-氟代脱氧葡萄糖(FDG)的动态分析表明，自由基的形成和谷氨酸的释放对脑损伤可逆性的贡献是不同的。这种方法使我们能够在严格控制的条件下阐明药物对神经元损伤的影响。作为另一项研究，肿瘤的耐缺氧也可以与非肿瘤组织的缺氧进行比较。根据本工作的结果，可以成功地进行低氧肿瘤治疗性放射性药物的选择性放射治疗。

项目成果

Lewis,J.S.: "Evaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor model."J Nucl Med. 40(1). 177-183 (1999)

Lewis, J.S.：“在缺氧肿瘤模型中体外和体内评估 64Cu-ATSM。”J Nucl Med。

Lewis, J.S., et al.: "Copper-64-diacetyl-bis (N4-methylthiosemicarbazone) : An agent for radiotherapy."Proc Natl Acad Sci. 98 (3). 1206-1211 (2001)

Lewis, J.S. 等人：“Copper-64-di乙酰基-双（N4-甲硫缩氨基脲）：放射治疗剂。”Proc Natl Acad Sci。

Murata,T.: "Dynamic changes in glucose metabolism induced by thiamine deficiency and its replenishment as revealed by a positron autoradiography technique using rat living brain slices"J Neurol Sci. 164(1). 29-36 (1999)

Murata,T.：“通过使用大鼠活体脑切片的正电子放射自显影技术揭示了硫胺素缺乏及其补充引起的葡萄糖代谢的动态变化”J Neurol Sci。

Hosokawa, R., et al.: "Myocardial metabolism of 123I-BMIPP in a canine model with ischemia : implications of perfusion-metabolism mismatch on SPECT images in patients with ischemic heart disease."J Nucl Med. 40 (3). 471-8 (1999)

Hosokawa, R. 等人：“缺血性犬模型中 123I-BMIPP 的心肌代谢：灌注-代谢不匹配对缺血性心脏病患者 SPECT 图像的影响。”J Nucl Med。

Lewis,J.S.: "Copper-64-diacetyl-bis (N4-methylthiosemicarbazone) : An agent for radiotherapy."Proc Natl Acad Sci. 98(3). 1206-1211 (2001)

Lewis, J.S.：“铜-64-二乙酰基-双（N4-甲硫缩氨基脲）：放射治疗剂。”Proc Natl Acad Sci。