Role of IKKβ in obesity and atherosclerosis

IKKβ 在肥胖和动脉粥样硬化中的作用

• 批准号: 10008480
• 负责人: Changcheng Zhou
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10008480
• 关键词: Ablation; Adipocytes; Adipose tissue; Antisense Oligonucleotides; Atherosclerosis; Blood Vessels; Cells; Chronic; Consumption; Country; Development; Diabetes Mellitus; Diet; Disease; Epidemic; Goals; High Fat Diet; Human; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Link; Metabolic Diseases; Molecular; Mus; Myelogenous; Natural Immunity; Obesity; Overnutrition; Pathway interactions; Pharmacology; Phosphotransferases; Regulation; Reporting; Resistance; Role; Signal Transduction; Smooth Muscle Myocytes; System; Testing; Therapeutic; adipocyte differentiation; atherogenesis; cardiometabolism; gain of function; in vivo; inhibitor/antagonist; innovation; interest; lipid biosynthesis; loss of function; macrophage; mouse model; novel; novel strategies; obesity development; population health; precursor cell; progenitor; public health relevance; response; therapeutic target; vascular inflammation

 DESCRIPTION (provided by applicant): Obesity is associated with a state of chronic inflammation that is thought to be a major contributor to diabetes and atherosclerosis. Many inflammatory pathways that contribute to the development of insulin resistance and atherosclerosis are regulated by IKKβ/NF-κB signaling. However, the role of IKKβ in metabolic disorders and atherosclerosis remains elusive. Our initial studies showed that IKKβ deficiency (driven by a SM22Cre-IKKβ- flox system) in smooth muscle cells (SMCs) rendered mice resistant to the development of diet-induced obesity, metabolic disorders, and atherosclerosis. We made the novel finding that SM22 is expressed in primary adipose stromal vascular (SV) cells and IKKβ positively regulates adipogenesis, indicating that chronic inflammation might be an important initial trigger for the adipocyte differentiation in response to high-fat diet consumption. Our central hypothesis is that IKKβ is essential for adipogenesis and atherogenesis, and that high-fat diet-induced IKKβ activation promotes adipocyte differentiation and adipose inflammation, leading to increased obesity, insulin resistance, and atherosclerosis. Three specific aims are proposed: (1) Define the role of IKKβ in the regulation of murine and human adipocyte differentiation in response to overnutrition; (2) Determine the contribution of adipocyte IKKβ to the development of obesity-associated insulin resistance and atherosclerosis; and (3) Determine the impact of pharmacological inhibition of IKKβ by antisense oligonucleotides on diet-induced obesity and atherosclerosis. The proposed studies will define the role of IKKβ in adipogenesis and atherogenesis and will reveal a critical link between overnutrition, inflammation, and cardiometabolic disease. Our studies will also provide strong evidence for use of appropriate IKKβ inhibitors as an innovative therapeutic strategy to treat obesity and cardiometabolic disease.

 描述（由申请人提供）：肥胖与慢性炎症状态有关，慢性炎症被认为是糖尿病和动脉粥样硬化的主要原因。IKKβ/NF-κB信号通路参与了多种炎症通路的调节，这些炎症通路参与了胰岛素抵抗和动脉粥样硬化的发生发展。然而，IKKβ在代谢紊乱和动脉粥样硬化中的作用仍然是难以捉摸的。我们的初步研究表明，平滑肌细胞（SMC）中的IKKβ缺陷（由SM 22 Cre-IKK β- flox系统驱动）使小鼠对饮食诱导的肥胖、代谢紊乱和动脉粥样硬化的发展具有抵抗力。我们发现SM 22在原代脂肪基质血管（SV）细胞中表达，IKKβ正调控脂肪生成，表明慢性炎症可能是高脂饮食引起脂肪细胞分化的重要初始触发因素。我们的中心假设是IKKβ对脂肪形成和动脉粥样硬化形成至关重要，高脂饮食诱导的IKKβ活化促进脂肪细胞分化和脂肪炎症，导致肥胖、胰岛素抵抗和动脉粥样硬化增加。提出了三个具体的目标：（1）确定IKKβ在调节小鼠和人类脂肪细胞分化中的作用，以响应营养过剩;（2）确定脂肪细胞IKKβ对肥胖相关胰岛素抵抗和动脉粥样硬化发展的贡献;（3）确定通过反义寡核苷酸对IKKβ的药理学抑制对饮食诱导的肥胖和动脉粥样硬化的影响。拟议的研究将确定IKKβ在脂肪形成和动脉粥样硬化形成中的作用，并将揭示营养过剩、炎症和心脏代谢疾病之间的关键联系。我们的研究还将为使用适当的IKKβ抑制剂作为治疗肥胖和心脏代谢疾病的创新治疗策略提供强有力的证据。

项目成果

The Role of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease.

• DOI: 10.3390/cells11111834
• 发表时间: 2022-06-03
• 期刊: Cells
• 影响因子: 6

Pregnane X Receptor Mediates Atherosclerosis Induced by Dicyclohexyl Phthalate in LDL Receptor-Deficient Mice.

• DOI: 10.3390/cells11071125
• 发表时间: 2022-03-26
• 期刊: Cells
• 影响因子: 6
• 作者: Liu J;Hernandez R;Li X;Meng Z;Chen H;Zhou C
• 通讯作者: Zhou C

Paternal phthalate exposure-elicited offspring metabolic disorders are associated with altered sperm small RNAs in mice.

• DOI: 10.1016/j.envint.2023.107769
• 发表时间: 2023-02
• 期刊: ENVIRONMENT INTERNATIONAL
• 影响因子: 11.8
• 作者: Liu, Jingwei;Shi, Junchao;Hernandez, Rebecca;Li, Xiuchun;Konchadi, Pranav;Miyake, Yuma;Chen, Qi;Zhou, Tong;Zhou, Changcheng
• 通讯作者: Zhou, Changcheng

Diabetes and Its Cardiovascular Complications: Comprehensive Network and Systematic Analyses.

• DOI: 10.3389/fcvm.2022.841928
• 发表时间: 2022
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Wu H;Norton V;Cui K;Zhu B;Bhattacharjee S;Lu YW;Wang B;Shan D;Wong S;Dong Y;Chan SL;Cowan D;Xu J;Bielenberg DR;Zhou C;Chen H
• 通讯作者: Chen H