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（通过应用程序证明）：肥胖症与慢性状态有关，而慢性病和动脉粥样硬化途径有助于胰岛素抵抗和动脉粥样硬化的发展。 IKKβ在代谢性疾病中的作用和动脉粥样硬化难以捉摸的n。 SM22在原发性脂肪基质血管（SV）EL和IKKβ蛇毒物质中表达，这表明慢性可能是脂肪细胞Ntiation的重要初始触发因素，以响应高脂饮食构建，促进了脂肪细胞的脂肪差异和脂肪差异。提出了肥胖，胰岛素抵抗和动脉粥样硬化的目的。 3）确定IKKβ通过药理学对IKKβ的hivation的影响。治疗肥胖和心脏代谢ASE的策略。

项目成果

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

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

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