CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH: PROJECT 4

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 这项提议的目的没有改变。它们旨在解决这样的假设：在高血糖条件下，醛糖还原酶(AR)增加葡萄糖代谢，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)，从而促进巨噬细胞激活和动脉粥样硬化形成。现已证实，巨噬细胞源性泡沫细胞中过度的胆固醇积聚导致内质网应激并激活UPR。最近，这一途径已经成为动脉粥样硬化和糖尿病研究中的一个统一主题，而UPR被认为是胰岛素抵抗的主要原因。尽管有这些进展，但导致内质网应激激活的机制以及激活内质网应激对巨噬细胞促炎反应和泡沫细胞形成的特定后果尚不清楚。具体地说，我们提出： 1.研究高糖是否促进胆固醇负荷巨噬细胞泡沫细胞的形成、细胞因子的产生和细胞的凋亡。 2.确定高糖是否通过触发UPR来调节胆固醇诱导的巨噬细胞活化。 3.阐明UPR活化在糖尿病小鼠细胞因子产生和动脉粥样硬化病变形成中的作用。

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.