An integrated experimental and computational model of brain microvascular endothelial cell glucose metabolism and transport

阿尔茨海默病可能部分是由脑血管的变化引起的。同时具有低胆固醇和高胆固醇的人患阿尔茨海默病的风险增加。然而，目前还不清楚血胆固醇是如何影响脑血管的。早期的研究表明，低胆固醇会导致脑血管中的细胞使用更多的糖，这意味着它们向大脑传递的糖更少。由于大脑中的低糖也是阿尔茨海默氏症的迹象，因此，低胆固醇导致的脑血管变化可能通过降低脑糖水平而导致阿尔茨海默氏症。在这项研究中，研究人员将进行实验，并使用计算机模型分析他们的结果，以了解胆固醇如何改变脑血管将糖输送到大脑的方式。调查人员还将邀请本科生在他们的实验室进行研究，调查人员将向当地高中生传授脑血管、胆固醇和阿尔茨海默氏症的知识。该项目将创造研究阿尔茨海默病的新方法，并可能导致治疗早期阿尔茨海默病的新药。阿尔茨海默病患者大脑中的葡萄糖代谢减少，可能是由于脑微血管内皮细胞(BMEC)减少葡萄糖运输。血管内皮细胞等内皮细胞在胆固醇等血液代谢物发生变化的情况下会出现功能障碍。中年高胆固醇会增加患阿尔茨海默氏症的风险，而低胆固醇也会增加晚年患阿尔茨海默病的风险。因此，了解高胆固醇和低胆固醇对BMEC葡萄糖转运的影响是非常必要的。研究人员的实验和计算分析表明，膜胆固醇降低导致BMEC减少葡萄糖转运，增加糖酵解代谢，上调胆固醇合成，并降低线粒体代谢。这些数据表明，胆固醇耗竭的BMEC改变了他们的系统新陈代谢。因此，本项目的目标是利用综合的实验和计算模型来研究膜胆固醇降低如何影响BMEC的葡萄糖代谢和转运。完成后，这些研究将为研究整合的BMEC葡萄糖代谢和运输提供新的实验和计算模型，并阐明胆固醇和葡萄糖运输之间的机制联系，为神经退行性疾病的胆固醇和降胆固醇疗法提供新的见解。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Alzheimer’s disease may be partially caused by changes in brain blood vessels. People who have both low and high blood cholesterol are at increased risk of developing Alzheimer’s disease. However, it is not clear how blood cholesterol affects brain blood vessels. Early studies suggest that low cholesterol causes cells in brain blood vessels to use more sugar, which means that they pass less sugar on to the brain. Since low sugar in the brain is also a sign of Alzheimer’s disease, it is possible that changes in brain blood vessels due to low cholesterol may contribute to Alzheimer's disease by lowering brain sugar levels. In this research, the investigators will conduct experiments and analyze their results using computer models to learn how cholesterol changes the way that brain blood vessels pass sugar into the brain. The investigators will also engage undergraduate students to do research in their laboratories, and the investigators will teach local high school students about brain blood vessels, cholesterol, and Alzheimer’s disease. This project will create new methods to study Alzheimer’s disease and could lead to new drugs to treat early Alzheimer’s disease.Glucose metabolism is reduced in the brains of patients with Alzheimer’s disease, perhaps due to reduced glucose transport by brain microvascular endothelial cells (BMEC). Endothelial cells such as BMEC become dysfunctional in conditions of altered blood metabolites, like cholesterol. The risk of Alzheimer’s disease increases with high cholesterol in mid-life yet also increases with low cholesterol later in life. It is therefore imperative to understand how both high and low cholesterol impact BMEC glucose transport. The investigator's experimental and computational analyses show that decreased membrane cholesterol causes BMEC to reduce glucose transport, increase glycolytic metabolism, upregulate cholesterol synthesis, and decrease mitochondrial metabolism. These data suggest that cholesterol-depleted BMEC shift their systemic metabolism. Therefore, the goal of this project is to investigate how decreased membrane cholesterol affects BMEC glucose metabolism and transport using integrated experimental and computational models. When completed, these studies will provide new experimental and computational models for studying integrated BMEC glucose metabolism and transport, as well as elucidate the mechanistic link between cholesterol and glucose transport to provide new insight into cholesterol and cholesterol-lowering therapies in neurodegenerative disease.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.