CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: PROJECT 4

糖尿病和肥胖研究卓越中心：项目 4

• 批准号: 8360415
• 负责人: Oleg A Barski
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360415
• 关键词: Address; Aldehyde Reductase; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Cholesterol; Diabetes Mellitus; Diabetic mouse; Foam Cells; Funding; Glucose; Grant; Hyperglycemia; Insulin Resistance; Macrophage Activation; National Center for Research Resources; Obesity; Pathway interactions; Principal Investigator; Production; Proteins; Research; Research Infrastructure; Research Project Grants; Resources; Source; United States National Institutes of Health; atherogenesis; cost; cytokine; design; endoplasmic reticulum stress; glucose metabolism; hypercholesterolemia; macrophage; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The aims of this proposal have not changed. They are designed to address the hypothesis that under hyperglycemic conditions, increased metabolism of glucose by aldose reductase (AR) exacerbates hypercholesterolemia-induced endoplasmic reticulum (ER) stress and unfolded protein response (UPR), and thereby promotes macrophage activation and atherogenesis. It has been established that accumulation of excessive cholesterol in macrophage-derived foam cells leads to ER stress and activates UPR. This pathway has recently emerged as a unifying theme in atherosclerosis and diabetes research and UPR has been suggested to be the major cause of insulin resistance. Despite these advances, the mechanisms leading to the activation of ER stress and specific consequences of its activation for macrophage proinflammatory response and foam cell formation is not known. Specifically, we proposed: 1. Examine whether high glucose increases foam cell formation, cytokine production and apoptosis in cholesterol-loaded macrophages. 2. Determine whether high glucose modulates cholesterol-induced macrophage activation by triggering UPR. 3. Delineate the contribution of UPR activation to cytokine production and atherosclerotic lesion formation in diabetic mice.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 这项建议的目的没有改变。它们旨在解决以下假设：在高血糖条件下，通过醛糖还原酶（AR）增加的葡萄糖代谢加剧高胆固醇血症诱导的内质网（ER）应激和未折叠蛋白反应（UPR），从而促进巨噬细胞活化和动脉粥样硬化形成。已经确定，巨噬细胞源性泡沫细胞中过量胆固醇的积累导致ER应激并激活UPR。该途径最近已成为动脉粥样硬化和糖尿病研究的统一主题，并且UPR已被认为是胰岛素抵抗的主要原因。尽管有这些进展，但导致ER应激激活的机制及其激活巨噬细胞促炎反应和泡沫细胞形成的具体后果尚不清楚。具体而言，我们建议： 1.检查高葡萄糖是否增加泡沫细胞形成，细胞因子产生和胆固醇负载的巨噬细胞凋亡。 2.确定高葡萄糖是否通过触发UPR调节胆固醇诱导的巨噬细胞活化。 3.描述UPR激活对糖尿病小鼠细胞因子产生和动脉粥样硬化病变形成的贡献。