Astrocyte regulation of cerebral blood flow during hypoglycemia

低血糖期间星形胶质细胞对脑血流的调节

• 批准号: 10518803
• 负责人: ERIC A NEWMAN
• 金额: $ 38.56万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518803
• 关键词: Acids; Adenosine; Animals; Astrocytes; Blood Glucose; Blood Vessels; Blood capillaries; Brain; Brain Injuries; Calcium Signaling; Caliber; Cells; Cerebrovascular Circulation; Cerebrum; Cessation of life; Cognitive deficits; Coma; Complications of Diabetes Mellitus; Deoxyglucose; Fluorescent Dyes; Glucose; Health; Human; Hyperemia; Hypoglycemia; Impaired cognition; Injections; Inositol; Insulin; Knockout Mice; Lead; Measures; Mediating; Mediator of activation protein; Membrane; Modeling; Monitor; Mus; Neurons; Oxygen; Process; Prostaglandins; Purinergic P1 Receptors; Regulation; Research; Risk; Signal Transduction; Somatosensory Cortex; Testing; Unconscious State; Vasodilator Agents; Vibrissae; Work; antagonist; arteriole; awake; deprivation; diabetic patient; experimental study; inhibitor; neuronal cell body; neurovascular coupling; novel; receptor; response; two photon microscopy

Project Summary Hypoglycemia is a serious complication of diabetes resulting from insulin treatment which can lead to cognitive deficits, brain damage, loss of consciousness and death. A primary response to hypoglycemia is an increase in cerebral blood flow (CBF), which augments the supply of glucose to the brain. A hypoglycemia-induced increase in adenosine in the brain is thought to mediate CBF increases. However, astrocytes, which release vasodilating agents and regulate vascular tone, might also contribute to hypoglycemia-induced vessel dilation and CBF increases. This novel hypothesis, that astrocytes contribute to hypoglycemia-induced CBF increases, is supported by our preliminary experiments. We will test this hypothesis by simultaneously monitoring astrocyte Ca2+ signaling and blood vessel diameter in the somatosensory cortex of awake mice with two-photon microscopy as blood glucose is lowered by insulin administration. The hypothesis will be tested in the following aims. Aim 1. Test the hypothesis that astrocytes mediate hypoglycemia-induced vessel dilation. The relation between blood glucose, astrocyte Ca2+ signaling, and vessel diameter will be determined as blood glucose is lowered by insulin administration in control mice and in IP3R2 KO mice, where astrocyte Ca2+ signaling is reduced. As suggested by our preliminary results, we anticipate that vessel dilation will be reduced in IP3R2 KO animals, demonstrating that astrocytes contribute to hypoglycemia-induced vessel dilation. Aim 2. Test the hypothesis that adenosine evokes Ca2+ increases in astrocytes and the release of vasodilating prostaglandins (PGs) and epoxyeicosatrienoic acids (EETs) during hypoglycemia. Adenosine mediates hypoglycemia-induced CBF increases. We will test the hypothesis that adenosine dilation of vessels acts in part by stimulating astrocytes and evoking astrocyte Ca2+ increases. PGs and EETs are released from astrocytes and dilate cerebral vessels. We will test whether one or both of these astrocyte vasodilators contribute to hypoglycemia-induced vessel dilation. Aim 3. Determine whether neurovascular coupling is altered during hypoglycemia. Increases in neuronal activity evoke local increases in CBF. This response, termed functional hyperemia, supplies active neurons with needed glucose and oxygen. We will test whether vessel dilation evoked by whisker stimulation is altered during hypoglycemia.

项目摘要 低血糖症是糖尿病的一种严重并发症，由胰岛素治疗引起， 导致认知缺陷、脑损伤、意识丧失和死亡。的初级应答 低血糖导致脑血流量（CBF）增加，从而增加了脑血流量的供应。 葡萄糖进入大脑低血糖引起的脑内腺苷增加被认为 介导CBF增加。然而，星形胶质细胞，释放血管扩张剂和调节 血管张力，也可能有助于低血糖诱导的血管扩张和CBF 增大这一新的假设，即星形胶质细胞有助于低血糖诱导的脑血流 这一点得到了我们初步实验的支持。我们将通过以下方式检验这一假设： 同时监测星形胶质细胞Ca2+信号和血管直径， 清醒小鼠血糖降低时体感皮层双光子显微镜观察 通过胰岛素给药。该假设将在以下目标中进行检验。 目标1.验证星形胶质细胞介导低血糖诱导的血管生成的假设 膨胀血糖、星形胶质细胞Ca 2+信号和血管直径之间的关系将 当在对照小鼠和IP3R2中通过胰岛素施用降低血糖时， KO小鼠，其中星形胶质细胞Ca2+信号传导减少。正如我们的初步结果所表明的那样， 我们预期IP3R2基因敲除动物的血管扩张将减少，这表明 星形胶质细胞有助于低血糖诱导的血管扩张。 目标2.检验腺苷引起星形胶质细胞中Ca2+增加的假设， 释放血管舒张性前列腺素（PGs）和环氧二十碳三烯酸（Ehrs） 在低血糖期间。腺苷介导低血糖诱导的CBF增加。我们将测试 腺苷扩张血管部分是通过刺激星形胶质细胞起作用的假设， 引起星形胶质细胞Ca2+增加。PGs和Ehrs从星形胶质细胞释放并扩张 脑血管我们将测试这些星形胶质细胞血管扩张剂中的一种或两种是否有助于 低血糖诱导的血管扩张。 目标3。确定低血糖时神经血管耦合是否改变。 神经元活动的增加引起CBF的局部增加。这种反应称为功能性反应， 充血，为活跃的神经元提供所需的葡萄糖和氧气。我们将测试 在低血糖期间，由触须刺激引起的血管扩张发生改变。