Targeting Hypoxia-Inducible Factor (HIF) as a Therapeutic Strategy for CNS Disorders
Targeting Hypoxia-Inducible Factor (HIF) as a Therapeutic Strategy for CNS Disorders
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DOI：
10.2174/1568007053005154
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发表时间：
2005-01-01
影响因子：
3
通讯作者：
Barone, Maria Cecilia
中科院分区：
文献类型：
--
作者：
Freeman, Robert S.;Barone, Maria Cecilia
当氧气供应量下降到维持正常代谢率所需的水平以下时，就会发生缺氧。由于其高代谢活性，大脑对缺氧高度敏感。大脑中严重或长时间的缺氧会导致与中风和各种其他神经元疾病相关的损伤。相反，在许多脑肿瘤的核心中发现的极端缺氧环境支持肿瘤的生长和肿瘤细胞的存活。暴露于短暂或中度缺氧的正常细胞通常能够适应缺氧条件，主要是通过激活缺氧诱导转录因子HIF。HIF调节基因编码参与能量代谢、细胞存活、红细胞生成、血管生成和血管调节的蛋白质。在缺氧或缺氧和缺血的许多情况下，HIF靶基因的诱导可能是有益的。当这些相同的损伤发生在通常血管化不良的组织中时，例如视网膜和实体瘤的核心，诱导相同的HIF靶基因可以促进疾病。对调节HIF氧敏感性的分子机制的主要新见解，以及在开发操纵HIF活性的化合物中，迫使人们认真考虑将HIF作为与缺氧相关的各种CNS疾病的治疗靶点。
Hypoxia occurs when oxygen availability drops below the levels necessary to maintain normal rates of metabolism. Because of its high metabolic activity, the brain is highly sensitive to hypoxia. Severe or prolonged oxygen deprivation in the brain contributes to the damage associated with stroke and a variety of other neuronal disorders. Conversely, the extreme hypoxic environment found in the core of many brain tumors supports the growth of the tumor and the survival of tumor cells. Normal cells exposed to transient or moderate hypoxia are generally able to adapt to the hypoxic conditions largely through activation of the hypoxia-inducible transcription factor HIF. HIF-regulated genes encode proteins involved in energy metabolism, cell survival, erythropoiesis, angiogenesis, and vasomotor regulation. In many instances of hypoxia or hypoxia and ischemia, the induction of HIF target genes may be beneficial. When these same insults occur in tissues that are normally poorly vascularized, such as the retina and the core of solid tumors, induction of the same HIF target genes can promote disease. Major new insights into the molecular mechanisms that regulate the oxygen-sensitivity of HIF, and in the development of compounds with which to manipulate HIF activity, are forcing serious consideration of HIF as a therapeutic target for diverse CNS disorders associated with hypoxia.