Angiogenic Response to Hypoxia and Ketosis in Rat Brain

大鼠脑中缺氧和酮症的血管生成反应

• 批准号: 7787036
• 负责人: Joseph Charles Lamanna
• 金额: $ 39.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787036
• 关键词: 3-nitropropionate; Age; Aging; Attenuated; Behavioral; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Brain Hypoxia; Carbohydrates; Cerebrovascular Circulation; Cerebrum; Citric Acid Cycle; Coupling; Degradation Pathway; Diet; Energy Metabolism; Enzymes; Fatty acid glycerol esters; Functional disorder; Glucose; Glucose Transporter; Homeostasis; Hypoxia; Image; Intraventricular Infusion; Ketone Bodies; Ketones; Ketoses; Ketosis; Mammalian Cell; Measures; Metabolic; Molecular; Motor; Nerve Degeneration; Outcome; Oxidative Stress; Oxygen; Performance; Physiological; Play; Process; Procollagen-Proline Dioxygenase; Proteins; Rattus; Recovery; Role; SLC2A1 gene; Signal Transduction; Signaling Molecule; Stimulus; Stroke; Stroke prevention; Succinate Dehydrogenase; Succinates; System; Testing; Up-Regulation; Vascular Endothelial Growth Factors; aged; aging brain; angiogenesis; base; brain metabolism; capillary; cognitive function; density; feeding; glucose metabolism; hypoxia inducible factor 1; improved; inhibitor/antagonist; ketogenic diet; neuroprotection; neurovascular unit; preconditioning; public health relevance; response; stroke recovery; transcription factor; young adult

DESCRIPTION (provided by applicant): Neurodegeneration associated with oxidative stress limits recovery from stroke and other pathophysiological challenges. There are many physiological factors that play a role in recovery from oxidative stress and survival such as those related to stabilization of energy metabolism and vascular integrity. For example, prolonged mild hypoxia initiates a sequence of vascular and metabolic adaptations in brain. Angiogenesis and the resultant increased capillary density is a fundamental aspect of the hypoxic adaptation process. In the aged brain, however, there is an apparent deficiency in glucose metabolism and lack of hypoxic response. Cerebral blood flow (CBF) and metabolic rate for glucose (CMRglu) as well as the coupling between CBF and CMRglu are known to decline as a function of age, suggesting dysfunction of the neurovascular unit. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates adaptive responses to the lack of oxygen in mammalian cells and has multiple functions related to cellular homeostasis and survival, such as the upregulation of VEGF and EPO, known neuroprotective molecules. In the aged brain, the HIF-1 response to hypoxia is severely attenuated. The inability to stabilize HIF-1 is consistent with the deleterious outcomes with even mild hypoxia suffered by the aged brain that the young adult brain can overcome. We have recently shown accumulation of HIF-1a (without hypoxic stimulation) and increased vascular density in young mature rat brain in rats made ketotic through a ketogenic diet. The increased blood ketones were accompanied by up-regulation of the primary substrate transporters for glucose (GLUT1) and ketones (monocarboxylates; MCT1) at the blood-brain barrier. We intend to determine if similar responses can be elicited in the ketotic, aged rat brain. Ketone bodies are alternate energy substrates to glucose and are signaling molecules that stabilize glucose metabolism by relieving metabolic blocks. We will investigate if ketosis (via a ketogenic diet) in the aged rat results in a similar angiogenic response as the younger adult brain and test if there is improved adaptation response to hypoxia. The common mechanism by which ketones act is most likely related through the stabilization of glucose metabolism and citric acid cycle intermediates resulting in increased brain succinate levels. Increased succinate levels result in inhibition of prolyl-hydroxylase (PHD), a key enzyme of the HIF-1a degradation pathway. Inhibition of PHD will result in greater accumulation of HIF-1a and should result in better tolerance to hypoxia as measured by molecular, structural and behavioral responses. PUBLIC HEALTH RELEVANCE: Neurodegeneration as a result of stroke and other pathophysiological challenges related to aging remains to be explored. We propose to investigate if ketosis, induced by ketogenic diet (low carbohydrate, high fat) results in improved adaptation response to hypoxia in aged rat brain. The ability to alter brain metabolism and produce neuroprotection by dietary adjustments would be a significant new strategy for stroke prevention and recovery.

描述（由申请人提供）：与氧化应激相关的神经变性限制了中风和其他病理生理学挑战的恢复。有许多生理因素在氧化应激恢复和生存中发挥作用，例如与能量代谢稳定和血管完整性相关的因素。例如，长期轻度缺氧会引发大脑一系列血管和代谢适应。血管生成和由此产生的毛细血管密度增加是缺氧适应过程的一个基本方面。然而，在衰老的大脑中，葡萄糖代谢明显不足，缺乏缺氧反应。已知脑血流量 (CBF) 和葡萄糖代谢率 (CMRglu) 以及 CBF 和 CMRglu 之间的耦合随着年龄的增长而下降，表明神经血管单元功能障碍。缺氧诱导因子-1 (HIF-1) 是一种转录因子，可调节哺乳动物细胞对缺氧的适应性反应，并具有与细胞稳态和生存相关的多种功能，例如上调 VEGF 和 EPO（已知的神经保护分子） 。在衰老的大脑中，HIF-1 对缺氧的反应严重减弱。无法稳定 HIF-1 与老年大脑所遭受的轻微缺氧的有害结果是一致的，而年轻人的大脑可以克服这一点。我们最近发现，通过生酮饮食进行酮症的年轻成熟大鼠大脑中 HIF-1a 的积累（无缺氧刺激）和血管密度增加。血酮增加伴随着血脑屏障处葡萄糖（GLUT1）和酮（单羧酸盐；MCT1）的主要底物转运蛋白的上调。我们打算确定是否可以在酮症、老年大鼠大脑中引起类似的反应。酮体是葡萄糖的替代能量底物，是通过缓解代谢障碍来稳定葡萄糖代谢的信号分子。我们将研究老年大鼠的酮症（通过生酮饮食）是否会导致与年轻成年大鼠相似的血管生成反应，并测试是否改善了对缺氧的适应反应。酮类作用的常见机制很可能与稳定葡萄糖代谢和柠檬酸循环中间体导致脑琥珀酸水平增加有关。琥珀酸水平升高会抑制脯氨酰羟化酶 (PHD)，这是 HIF-1a 降解途径的关键酶。抑制 PHD 将导致更多的 HIF-1a 积累，并且根据分子、结构和行为反应测量，应该会导致更好的缺氧耐受性。公共卫生相关性：中风和其他与衰老相关的病理生理学挑战导致的神经退行性疾病仍有待探索。我们建议研究生酮饮食（低碳水化合物、高脂肪）诱导的酮症是否会改善老年大鼠大脑对缺氧的适应反应。通过饮食调整改变大脑代谢并产生神经保护的能力将是中风预防和恢复的重要新策略。