Mechanisms of Atherogenesis in Insulin Resistance

2型糖尿病(T2D)患者心血管疾病的显著增加要求 综合心脏代谢方法。使用这种方法，PPG团队进行了高度互动和 过去10年的高效协作，并计划向前迈进，探索共同的 不同类型细胞中促进心脏代谢的转录和信号机制 疾病。这一目标将通过3个项目之间持续的协同互动来实现 核心A项目1(TABAS)将探索肝细胞中常见的上游CaMKII/MK2途径 巨噬细胞(MS)和巨噬细胞分别促进胰岛素抵抗和斑块进展--以及如何 HC途径通过全身性胰岛素抵抗放大M途径。该项目有一个 基于机制的治疗/转换组件，涉及与Tall博士和 阿奇利。例如，Tabas和Tall博士将探索这一新发现，即MCaMKII/MK2途径- 调节LXR，从而损害一个关键的动脉粥样硬化保护过程，即泡沫化。项目2(TALL)将探索 T39在肝细胞癌、皮损MS和脂肪细胞中的作用在Hcs和MS中，T39改变LXR激活促进 并阻断MLXR对动脉粥样硬化的抑制作用。因此，阻断T39 抑制动脉粥样硬化和脂肪肝。Tall&Tabas博士与研究MLXR在 抑制T39缺陷小鼠的动脉粥样硬化(上图)。在脂肪细胞中，T39抑制褐变，它 可能会促进胰岛素抵抗和动脉粥样硬化。该机制涉及PPAR1的下调， 将与阿奇利博士一起探索这一问题。项目3(Accili)解决了T2D疗法中的一个关键问题， 也就是说，噻唑烷二酮(TZD)的使用明显受到心源性液体滞留和骨丢失的限制。Dr。 Accili发现TZDS的靶标PPAR可以去乙酰化，这改变了它的功能和反应 去TZDS。当TZD用于表达脱乙酰化突变体PPAR(“2KR”)的胰岛素抵抗小鼠时， 胰岛素增敏的好处仍然存在，但防止了液体滞留和骨丢失。与Tabas博士和 Accili博士将调查这些发现与动脉粥样硬化的相关性，并将探索 机制。例如，Accili和Tabas博士发现2KR小鼠的MS显著增强 泡沫症，这预示着斑块进展的减缓。2KR小鼠也表现出脂肪褐变，并且 Accili&Tall博士将评估这对动脉粥样硬化形成的影响。核心A(王和伟博士)将提供 为PPG的所有动脉粥样硬化研究提供必要的支持和整合，并将提供 提供统计和生物信息支持，以确保所有项目的严密性和可重复性。总而言之，通过 PPG PI之间的协同作用，这些新的研究将揭示重要的新概念 与心脏代谢性疾病的综合病理生理学相关的治疗靶点。

The marked increase in cardiovascular disease in patients with type 2 diabetes (T2D) demands an integrated cardiometabolic approach. Using this approach, the PPG team has had a highly interactive and productive collaboration for the last 10 years and plans to move forward to explore common transcriptional and signaling mechanisms in distinct cell types that contribute to cardiometabolic disease. This goal will be achieved through continued synergistic interactions among the 3 projects and Core A. Project 1 (Tabas) will explore how a common upstream CaMKII/MK2 pathway in hepatocytes (HCs) and macrophages (Ms) promotes insulin resistance and plaque progression, respectively—and how the HC pathway amplifies the M pathway through systemic insulin resistance. The project has a mechanism-based therapeutic/translational component and involves key collaborations with Drs. Tall and Accili. For example, Drs. Tabas & Tall will explore the novel finding that the M CaMKII/MK2 pathway down- regulates LXR, thereby impairing a key atheroprotective process, efferocytosis. Project 2 (Tall) will explore the role of T39 in HCs, lesional Ms, and adipocytes. In HCs and Ms, T39 alters LXR activation to promote hepatosteatosis and block the suppressive effect of M LXR on atherosclerosis. Thus, blocking T39 suppresses both atherosclerosis and fatty liver. Drs. Tall & Tabas with study the role of M LXR in suppressing atherosclerosis in T39-deficient mice (above). In adipocytes T39 suppresses beiging, which may promote insulin resistance and atherosclerosis. The mechanism involves down-regulation of PPAR1, which will be explored with Dr. Accili. Project 3 (Accili) addresses a key problem in T2D therapeutics, namely, thiazolidinedione (TZD) use is markedly limited by cardiogenic fluid retention and bone loss. Dr. Accili discovered that PPAR, the target of TZDs, can be deacetylated, which alters it function and response to TZDs. When TZDs are used in insulin-resistant mice expressing deacetylated mutant PPAR ("2KR"), the insulin-sensitizing benefits remain but fluid retention and bone loss are prevented. With Drs. Tabas & Tall., Dr. Accili will investigate the relevance of these findings to atherosclerosis and will explore mechanism. For example, Drs. Accili & Tabas found that Ms from 2KR mice have markedly enhanced efferocytosis, which predicts decreased plaque progression. 2KR mice also display adipose beiging, and Drs. Accili & Tall will assess the impact of this on atherogenesis. Core A (Drs. Wang and Wei) will provide essential support and integration for all of the atherosclerosis studies of the PPG and will also provide statistical and bioinformatic support to ensure rigor and reproducibility for all projects. In summary, through synergistic interactions among the PPG PIs, these new studies will reveal important new concepts and therapeutic targets related to the integrated pathophysiology of cardiometabolic disease.