Astrocyte regulation of cerebral blood flow during hypoglycemia
Astrocyte regulation of cerebral blood flow during hypoglycemia
批准号:
10644005
负责人:
ERIC A NEWMAN
金额:
$38.56万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-07-01 至 2027-06-30
关键词:
AcidsAdenosineAnimalsAstrocytesBlood GlucoseBlood VesselsBlood capillariesBrainBrain InjuriesCalcium SignalingCellsCerebrovascular CirculationCerebrumCessation of lifeCognitive deficitsComaComplications of Diabetes MellitusDeoxyglucoseDiameterFluorescent DyesGlucoseHealthHumanHyperemiaHypoglycemiaITPR1 geneImpaired cognitionInjectionsInositolInsulinKnockout MiceLeadMeasuresMediatingMediatorMembraneModelingMonitorMusNeuronsOxygenPenetrationProcessProstaglandinsPurinergic P1 ReceptorsRegulationResearchRiskSignal TransductionSomatosensory CortexStarvationTestingUnconscious StateVasodilationVasodilator AgentsVibrissaeWorkantagonistarterioleawakedeprivationdiabetic patienteuglycemiaexperimental studyinhibitorinorganic phosphateneurovascular couplingnovelreceptorresponsetwo photon microscopy
中文摘要
项目摘要
低血糖是由胰岛素治疗引起的糖尿病的严重并发症,它可以
导致认知障碍、脑损伤、意识丧失和死亡。主要的回应
低血糖是脑血流量(CBF)的增加,这增加了血液中
葡萄糖进入大脑。低血糖引起的大脑中腺苷的增加被认为是
中度脑血流量增加。然而,星形胶质细胞释放血管扩张剂并调节
血管张力,也可能有助于低血糖诱导的血管扩张和脑血流
增加。这一新的假设认为,星形胶质细胞参与了低血糖诱导的脑血流
增加,得到了我们的初步实验的支持。我们将通过以下方式验证这一假设
星形胶质细胞钙信号与血管内径的同步监测
血糖降低时清醒小鼠体感皮层的双光子显微镜观察
通过注射胰岛素。这一假设将在以下目标中得到检验。
目的1.检验星形胶质细胞介导低血糖诱导血管的假说
扩张。血糖、星形胶质细胞钙信号与血管直径的关系
在对照组小鼠和IP3R2中通过注射胰岛素降低血糖时被测定
KO小鼠,星形胶质细胞钙信号减少。根据我们的初步结果,
我们预计IP3R2 KO动物的血管扩张将会减少,这表明
星形胶质细胞有助于低血糖诱导的血管扩张。
目的2.验证腺苷引起星形胶质细胞内钙增加的假设以及
血管扩张前列腺素(PGs)和环氧二十碳三烯酸(EETs)的释放
在低血糖期间。腺苷介导低血糖引起的脑血流量增加。我们将测试
腺苷扩张血管的假说部分是通过刺激星形胶质细胞和
引起星形胶质细胞钙离子浓度升高。PGS和EETs从星形胶质细胞释放出来并扩张
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对
低血糖引起的血管扩张。
目的3.确定低血糖时神经血管偶联是否发生改变。
神经元活动的增加会引起局部脑血流量的增加。这种反应被称为功能性反应
充血,为活跃的神经元提供所需的葡萄糖和氧气。我们将测试一下
在低血糖期间,胡须刺激引起的血管扩张会发生改变。
英文摘要
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.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
Astrocyte regulation of cerebral blood flow during hypoglycemia
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批准号:10518803
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项目类别:
-
资助金额:$38.56万
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财政年份:2022
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负责人:ERIC A NEWMAN
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