Effects of Hyperglycemia on Neuronal Activity, Cerebral Metabolism, and Amyloid-beta Levels

 描述（由申请人提供）：这个K 01辅导职业发展奖的目标是促进个人过渡到一个独立的调查员的角色，提供培训和指导，在葡萄糖代谢，阿尔茨海默病（AD）和2型糖尿病（T2 DM）领域。在大卫霍尔茨曼博士的指导下，并与约瑟夫卡尔弗，塔玛拉好时和科林尼科尔斯博士合作，候选人将研究高血糖对神经元活动和功能连接的作用，作为年龄和病理的函数。此外，候选人将在小动物神经成像，KATP通道生理学和AD相关研究领域接受广泛的教学和方法培训，以帮助实现研究申请中提出的目标。最近的研究表明，糖尿病患者或血糖水平升高的患者发生痴呆或AD所致痴呆的风险增加;然而，对葡萄糖代谢异常、T2 DM和AD之间的联系机制仍知之甚少。我们的初步数据表明，血糖水平的急性升高能够调节大脑中的淀粉样蛋白-β（Aβ）水平，为T2 DM和AD之间的联系提供了一种解释。然而，年龄或病理学如何影响血糖水平、脑功能和Aβ代谢之间的关系尚不清楚。此外，我们的工作表明，大脑葡萄糖代谢与细胞兴奋性，神经元活动和Aβ代谢通过以下途径耦合： ATP敏感性内向整流钾（KATP）通道;然而，研究KATP通道的慢性激活和细胞兴奋性增加是否是Aβ沉积增加的原因需要进一步研究。为了验证高血糖通过KATP通道调节Aβ水平以及这种关系作为年龄和病理学的函数而改变的假设，我们将研究以下目的：1）研究高血糖对健康大脑中神经元活性、突触可塑性和功能连接代谢的影响，作为正常衰老的函数。2)使用人类APP过表达的遗传模型，确定高血糖对神经元活动、网络连接和Aβ代谢的影响，作为AD病理学的函数。3)通过KATP通道活性的丧失，我们将在人APP过表达的小鼠模型中将葡萄糖敏感性与过度兴奋性解偶联，并确定它们对Aβ代谢和神经元活性的影响。

 DESCRIPTION (provided by applicant): The goal of this K01 Mentored Career Development Award is to facilitate the transition of the individual to the role of an independent investigator y providing training and mentorship in the areas of glucose metabolism, Alzheimer's disease (AD), and type-2-diabetes (T2DM). Under the mentorship of Dr. David Holtzman, and in collaboration with Drs. Joseph Culver, Tamara Hershey, and Colin Nichols, the candidate will investigate the role of hyperglycemia on neuronal activity and functional connectivity as a function of age and pathology. Additionally, the candidate will receive extensive didactic and methodological training in the areas of small animal neuroimaging, KATP channel physiology, and AD-related research to help accomplish the goals set forth in the research application. Recent studies suggest that individuals with diabetes or those with elevated blood glucose levels have an increased risk for developing dementia or dementia due to AD; however, the mechanisms linking aberrant glucose metabolism, T2DM, and AD remain poorly understood. Our preliminary data suggests that acute increases in blood glucose levels have the ability to modulate amyloid-β (Aβ) levels in the brain, providing one explanation for the link between T2DM and AD. Yet it is unclear how age or pathology impacts the relationship between blood glucose levels, brain function, and Aβ metabolism. Moreover, our work suggests cerebral glucose metabolism is coupled with cellular excitability, neuronal activity, and Aβ metabolism via ATP-sensitive, inward rectifying potassium (KATP) channels; however, investigating whether chronic activation of KATP channels and increased cellular excitability is responsible for increased Aβ deposition warrants further study. To test the hypothesis that hyperglycemia regulates Aβ levels by KATP channel modulation and that this relationship is altered as a function of age and pathology, we will examine the following Aims: 1) Investigate the effects of hyperglycemia on neuronal activity, synaptic plasticity, and functional connectivity metabolism in a healthy brain as a function of normal aging. 2) Determine the effects of hyperglycemia on neuronal activity, network connectivity, and Aβ metabolism as a function of AD pathology using a genetic model of human APP overexpression. 3) Through the loss of KATP channel activity, we will uncouple glucose sensitivity from hyperexcitability in a mouse model of human APP overexpression and determine their effects on Aβ metabolism and neuronal activity.