Targeting hypoxia-inducible mediators to manipulate human adipocyte phenotype

靶向缺氧诱导介质来操纵人类脂肪细胞表型

• 批准号: 9313252
• 负责人: ROBERT W O'ROURKE
• 金额: $ 33.82万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313252
• 关键词: Adipocytes; Adipose tissue; Anabolism; Attenuated; Biological Models; Cell Therapy; Data; Experimental Models; Functional disorder; Gene Expression; Genetic; Glucose; Goals; Hexosamines; Human; Hypoxia; In Vitro; Inflammation; Inflammation Process; Inflammatory Response; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic stress; Metabolism; Methods; Modification; Obesity; Obesity associated disease; Oxygen; Patients; Phenotype; Plant Roots; Process; Public Health; Role; Targeted Research; Testing; Tissues; Viral Vector; base; biological adaptation to stress; clinically relevant; differential expression; endoplasmic reticulum stress; fatty acid oxidation; gene therapy; human disease; human tissue; improved; innovation; knock-down; lipid biosynthesis; lipid metabolism; macrophage; metabolic phenotype; novel; public health relevance; response; small hairpin RNA; stress activated protein kinase; therapy development

DESCRIPTION (provided by applicant): Obesity is associated with a state of adipose tissue dysfunction characterized by increased inflammation and aberrant metabolism that underlies systemic metabolic disease. Hypoxia is a putative root cause of adipose tissue dysfunction in obesity. Our preliminary data demonstrate that hypoxia induces inflammation in human adipose tissue macrophages (ATM) and hexosamine biosynthesis (HBS) and lipogenesis in human adipocytes, and that endoplasmic reticulum stress (ERS) and stress-activated protein kinases (SAPK) regulate these processes. Our long-term goal is to develop novel cell-based therapy for metabolic disease based on genetic modification of adipocytes and ATM. Our proposal-specific goals are to define the effects of hypoxia on human adipocyte metabolism and ATM inflammatory responses, to define the role of ERS and SAPK activation in regulating these processes, to define the role of ATM in regulating adipocyte metabolism, and finally, to determine if genetic modification of human adipocytes and ATM to accomplish knockdown of HBS and SAPK- related molecules shifts adipocytes towards a favorable metabolic phenotype. Our central hypotheses are: that hypoxia induces metabolic dysfunction characterized by increased lipogenesis and HBS in adipocytes, directly as well as via hypoxia-induced ATM inflammation; that these processes are regulated by ERS and SAPK activation; and that genetic knockdown of HBS-related mediators in adipocytes and SAPK-related mediators in ATM will induce a favorable metabolic phenotype in adipocytes. Aim I will define the role of hypoxia in regulating ERS and metabolism in human adipocytes and determine if inhibition of HBS attenuates hypoxia- induced ERS and metabolic responses in adipocytes. Aim II will define the role of hypoxia in regulating human ATM inflammation and determine if SAPK mediator knockdown attenuates hypoxia-induced ATM inflammatory responses. Aim III will define the role of hypoxia-primed ATM in regulating adipocyte metabolism and determine if SAPK mediator knockdown in ATM attenuates hypoxia's effects on adipocyte metabolism. This proposal is significant because it will identify novel hypoxia-inducible mediators and mechanisms of adipose tissue dysfunction in human tissues that will lead to therapy for metabolic disease. This proposal is innovative because it develops a model system for genetic modification of human adipocytes and ATM with the goal of manipulating adipocytes towards a favorable metabolic phenotype.

描述（由申请人提供）：肥胖与脂肪组织功能障碍状态相关，其特征在于炎症增加和代谢异常，这是全身代谢疾病的基础。缺氧是肥胖症中脂肪组织功能障碍的假定根本原因。我们的初步数据表明，缺氧会引起人脂肪组织巨噬细胞（ATM）和己糖胺生物合成（HBS）的炎症以及人脂肪细胞的脂肪生成，并且内质网应激（ERS）和应激激活蛋白激酶（SAPK）调节这些过程。我们的长期目标是开发基于脂肪细胞和 ATM 基因修饰的新型细胞疗法来治疗代谢疾病。我们提案的具体目标是定义缺氧对人类脂肪细胞代谢和 ATM 炎症反应的影响，定义 ERS ​​和 SAPK 激活在调节这些过程中的作用，定义 ATM 在调节脂肪细胞代谢中的作用，最后，确定对人类脂肪细胞和 ATM 进行基因修饰以实现 HBS 和 SAPK 相关分子的敲低是否会使脂肪细胞转向有利的代谢表型。我们的中心假设是：缺氧会直接或通过缺氧诱导的 ATM 炎症诱导代谢功能障碍，其特征是脂肪细胞中脂肪生成和 HBS 增加；这些过程受 ERS ​​和 SAPK 激活的调节；脂肪细胞中 HBS 相关介质和 ATM 中 SAPK 相关介质的基因敲除将在脂肪细胞中诱导有利的代谢表型。目标我将定义缺氧在调节人类脂肪细胞 ERS ​​和代谢中的作用，并确定抑制 HBS 是否会减弱缺氧诱导的脂肪细胞 ERS ​​和代谢反应。目标 II 将定义缺氧在调节人类 ATM 炎症中的作用，并确定 SAPK 介质敲低是否会减弱缺氧诱导的 ATM 炎症反应。目标 III 将定义缺氧引发的 ATM 在调节脂肪细胞代谢中的作用，并确定 ATM 中 SAPK 介质的敲低是否会减弱缺氧对脂肪细胞代谢的影响。这项提议意义重大，因为它将确定新的缺氧诱导介质和人体组织中脂肪组织功能障碍的机制，从而治疗代谢疾病。该提案具有创新性，因为它开发了人类脂肪细胞和 ATM 基因改造的模型系统，其目标是操纵脂肪细胞达到有利的代谢表型。

项目成果

Effect of reversible intermittent intra-abdominal vagal nerve blockade on morbid obesity: the ReCharge randomized clinical trial.

可逆间歇性腹内迷走神经阻滞对病态肥胖的影响：ReCharge 随机临床试验。

• 发表时间: 2014-09-03
• 作者: Ikramuddin, Sayeed;Blackstone, Robin P;Brancatisano, Anthony;Toouli, James;Shah, Sajani N;Wolfe, Bruce M;Fujioka, Ken;Maher, James W;Swain, James;Que, Florencia G;Morton, John M;Leslie, Daniel B;Brancatisano, Roy;Kow, Lilian;O'Rourke, Robert
• 通讯作者: O'Rourke, Robert

Adipocytes promote pancreatic cancer cell proliferation via glutamine transfer.

脂肪细胞通过谷氨酰胺转移促进胰腺癌细胞增殖。

• 发表时间: 2016-09
• 作者: Meyer, Kevin A;Neeley, Christopher K;Baker, Nicki A;Washabaugh, Alexandra R;Flesher, Carmen G;Nelson, Barbara S;Frankel, Timothy L;Lumeng, Carey N;Lyssiotis, Costas A;Wynn, Michelle L;Rhim, Andrew D;O'Rourke, Robert W
• 通讯作者: O'Rourke, Robert W