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: 8247822
• 负责人: Joseph Charles Lamanna
• 金额: $ 38.86万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247822
• 关键词: 3-nitropropionate; Age; Aging; Attenuated; Behavioral; Blood; Blood - brain barrier anatomy; Blood Glucose; Blood Vessels; Blood capillaries; Brain; Brain Hypoxia; Carbohydrates; Cerebrovascular Circulation; Cerebrum; Citric Acid Cycle; Core-Binding Factor; Coupling; Degradation Pathway; Diet; Energy Metabolism; Enzymes; Fatty acid glycerol esters; Functional disorder; Glucose; Glucose Transporter; Health; 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; 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挑战的恢复。有许多生理因素在从氧化应激和生存中恢复（例如与能量代谢和血管完整性稳定相关的）中起作用。例如，长时间的轻度缺氧会引起大脑中一系列血管和代谢适应的序列。血管生成和由此产生的毛细血管密度增加是低氧适应过程的基本方面。然而，在老年大脑中，葡萄糖代谢和缺氧反应缺乏明显缺乏。众所周知，葡萄糖（CMRGLU）的脑血流（CBF）和代谢率以及CBF和CMRGLU之间的耦合会随着年龄的增长而下降，这表明神经血管单元的功能障碍。低氧诱导因子-1（HIF-1）是转录因子，可调节对哺乳动物细胞中缺乏氧的适应性反应，并且具有与细胞稳态和生存有关的多种功能，例如VEGF和EPO的上调，即已知的神经保护分子。在老年大脑中，HIF-1对缺氧的反应严重减弱。无法稳定HIF-1与年龄较小的大脑所遭受的轻度缺氧，年轻人大脑可以克服的有害结果是一致的。最近，我们显示了HIF-1A的积累（没有缺氧刺激）和大鼠年轻大鼠脑中血管密度增加，从而通过生酮饮食使酮分裂使酮分裂。血酮增加的伴随着葡萄糖（GLUT1）和酮（单羧酸盐； MCT1）的原代底物转运蛋白的上调。我们打算确定在酮科，老化的大鼠脑中是否可以引起相似的反应。酮体是葡萄糖的替代能底物，并且是通过缓解代谢块稳定葡萄糖代谢的信号分子。我们将研究老化大鼠的酮症（通过生酮饮食）是否会产生与年轻的成人大脑相似的血管生成反应，并测试是否对缺氧的适应反应得到改善。酮作用最有可能通过葡萄糖代谢和柠檬酸循环中间体稳定而导致脑琥珀酸水平升高的常见机制。琥珀酸水平升高会导致抑制羟基羟化酶（PHD），这是HIF-1A降解途径的关键酶。抑制博士学位将导致HIF-1A的积累更多，并且应通过分子，结构和行为反应来提高对缺氧的耐受性。公共卫生相关性：中风和其他与衰老有关的病理生理挑战的神经变性尚待探索。我们建议研究是否由生酮饮食（低碳水化合物，高脂肪）诱导的酮症会改善对老化大鼠脑缺氧的适应反应。改变大脑代谢并通过饮食调整产生神经保护作用的能力将是预防和恢复的重要新策略。

项目成果

Oxidative metabolism: glucose versus ketones.

氧化代谢：葡萄糖与酮。

• DOI: 10.1007/978-1-4614-7411-1_43
• 发表时间: 2013
• 期刊: Advances in experimental medicine and biology
• 作者: Prince,Allison;Zhang,Yifan;Croniger,Colleen;Puchowicz,Michelle
• 通讯作者: Puchowicz,Michelle

Impact of Aging on Metabolic Changes in the Ketotic Rat Brain: Glucose, Oxidative and 4-HNE Metabolism.

• DOI: 10.1007/978-3-319-91287-5_4
• 发表时间: 2018
• 期刊: Advances in experimental medicine and biology
• 作者: Yifan Zhang;Kui Xu;T. Kerwin;J. LaManna;M. Puchowicz

Diet-induced ketosis improves cognitive performance in aged rats.

• DOI: 10.1007/978-1-4419-1241-1_9
• 发表时间: 2010
• 期刊: ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
• 作者: Xu, Kui;Sun, Xiaoyan;Eroku, Bernadette O.;Tsipis, Constantinos P.;Puchowicz, Michelle A.;La Manna, Joseph C.
• 通讯作者: La Manna, Joseph C.

Decreased carbon shunting from glucose toward oxidative metabolism in diet-induced ketotic rat brain.

• DOI: 10.1111/jnc.12965
• 发表时间: 2015-02
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Zhang Y;Zhang S;Marin-Valencia I;Puchowicz MA
• 通讯作者: Puchowicz MA