Metabolic interactions in the vascular wall: an integrated experimental and computational approach

血管壁代谢相互作用：综合实验和计算方法

• 批准号: 10660336
• 负责人: Alisa S Morss Clyne
• 金额: $ 74.37万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660336
• 关键词: Adult; Affect; Alzheimer' s Disease; American; Arterial Fatty Streak; Biochemical Pathway; Biomedical Engineering; Blood; Blood Glucose; Blood Vessels; Brain; Calcium Signaling; Cardiovascular Diseases; Cell Communication; Cell Membrane Permeability; Cell model; Cells; Cellular Metabolic Process; Cholesterol; Coculture Techniques; Communities; Complex; Computer Analysis; Computer Models; Consumption; Data; Disease; Drug Interactions; Endothelial Cells; Endothelium; Engineering; Environment; Experimental Models; Exposure to; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Glucose; Glutamine; Goals; Growth Factor; Heart Diseases; Human; In Vitro; Individual; Ions; Isotopes; Light; Link; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Metabolic; Metabolic dysfunction; Metabolic syndrome; Metabolism; Methods; Modeling; Morbidity - disease rate; Nutrient; Organism; Patients; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Proliferating; Risk; Signal Transduction; Smooth Muscle Myocytes; Testing; Tissues; Triglycerides; Tunica Intima; Vascular Endothelial Cell; Vascular Endothelium; Vascular Smooth Muscle; blood lead; cardiovascular disorder risk; cardiovascular disorder therapy; cell type; computer program; design; experimental study; glucose metabolism; glucose uptake; in silico; in vivo; metabolic abnormality assessment; migration; mortality; novel; therapy design; tissue culture

Project Summary Nearly 1 in 3 American adults has metabolic syndrome, a complex disorder defined by elevations in blood sugar, cholesterol, and triglycerides. Patients with metabolic syndrome have a high cardiovascular disease risk due to interactions among the elevated blood metabolites. However, since we do not have good methods for studying integrated and interacting metabolic changes, we treat each metabolic abnormality individually. As a result, patients are often on multiple medications, potentially decreasing the ability of each drug to normalize blood metabolites and raising the risk for negative drug interactions. In this project, we propose a novel integrated experimental and computational bioengineering approach to study how metabolic abnormalities contribute to cardiovascular disease. Specifically, we will study metabolic interactions between endothelial cells, which line the inside of the blood vessels, and vascular smooth muscle cells, which contribute to cardiovascular disease when they change their function. We will engineer a computational isotope-assisted metabolic flux analysis (iMFA) model, which uses experimental mass spectrometry data to estimate intracellular metabolic fluxes and metabolite transport. The computational model will enable us to develop new hypotheses for and plan studies into how metabolic changes (from altered blood metabolites or therapies) affect the vascular wall. We hypothesize that EC metabolic dysfunction increases the transport of metabolites that promote VSMC to switch from a contractile to a synthetic phenotype. In turn, synthetic vSMC enhance EC metabolite transport to support proliferation. To explore this hypothesis, we will combine in vitro, in silico, and ex vivo studies to: 1) Determine how EC dysfunction in altered metabolic environments impacts metabolite transport; 2) Measure how altered metabolites synergistically shift vSMC to a synthetic phenotype; and 3) Investigate how EC-vSMC crosstalk impacts cell metabolism and phenotype in the vascular wall. We will start with single cell models of endothelial and vascular smooth muscle cells, which will simulate the diversity of human nutrient levels. We will the integrate the two cell types to understand their crosstalk in vitro, in silico, and ex vivo. At each step, we will relate metabolism to cell phenotype and function to link the model to cardiovascular disease. The computational iMFA model of integrated endothelial-vascular smooth muscle cell metabolism, transport, and function will enable us to develop new hypotheses for and plan studies into how metabolic changes from altered blood metabolites or therapies affect the vascular wall. By changing the parenchymal cell type, the model can then be extended to study vascular metabolic interactions in other tissues (e.g., brain) and shed light into other diseases in which integrated EC metabolism and transport (e.g., Alzheimer’s disease).

项目摘要 近三分之一的美国成年人患有代谢综合征，这是一种由血液升高定义的复杂疾病 糖，胆固醇和甘油三酸酯。代谢综合征患者的心血管疾病风险很高 由于血液代谢产物升高的相互作用。但是，由于我们没有很好的方法 研究综合和相互作用的代谢变化，我们单独处理每个代谢绝对。作为 结果，患者通常使用多种药物，可能会降低每种药物正常化的能力 血液代谢产物并增加了药物相互作用的风险。 在这个项目中，我们提出了一种新颖的综合实验和计算生物工程方法 研究代谢异常如何导致心血管疾病。具体来说，我们将研究代谢 内皮细胞之间的相互作用，这些细胞在血管内部和血管平滑肌之间进行相互作用 细胞改变功能时会导致心血管疾病。我们将设计 计算同位素辅助代谢通量分析（IMFA）模型，该模型使用实验质量 光谱数据以估计细胞内代谢通量和代谢产物转运。计算模型 将使我们能够为新陈代谢的变化开发新的假设和计划研究 代谢物或疗法）影响血管壁。 我们假设EC代谢功能障碍会增加促进VSMC的代谢产物的运输 从收缩式切换到合成表型。反过来，合成VSMC增强了EC代谢物转运 支持增殖。为了探讨这一假设，我们将在体外，在计算机中结合体外研究，从而：1） 确定改变代谢环境中的EC功能障碍如何影响代谢产物转运； 2）测量如何 改变的代谢产物合成将VSMC转移到合成表型。 3）研究EC-VSMC如何 串扰会影响血管壁中的细胞代谢和表型。 我们将从内皮和血管平滑肌细胞的单细胞模型开始，这将模拟 人类营养水平的多样性。我们将集成两种细胞类型，以了解其体外串扰， 在硅和ex Vivo中。在每个步骤中，我们都将新陈代谢与细胞表型和功能联系起来，以将模型与 心血管疾病。 综合内皮 - 血管平滑肌细胞代谢，运输，运输的计算IMFA模型 功能将使我们能够为新的假设开发新的假设和计划研究，以了解代谢如何从 血液代谢物或疗法改变会影响血管壁。通过更改副群细胞类型，该模型 然后可以扩展以研究其他组织（例如大脑）中的血管代谢相互作用 综合EC代谢和运输的其他疾病（例如，阿尔茨海默氏病）。