Extracellular matrix-adipocyte metabolic crosstalk and diabetes

细胞外基质-脂肪细胞代谢串扰与糖尿病

• 批准号: 10426242
• 负责人: ROBERT W O'ROURKE
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426242
• 关键词: 3-Dimensional; Adipocytes; Adipose tissue; Advanced Glycosylation End Products; Biology; CD36 gene; Cell Communication; Cell physiology; Cells; Central obesity; Collaborations; Communication; Communities; Complex; Data; Development; Diabetes Mellitus; Diabetic mouse; Disease; Engineering; Equilibrium; Extracellular Matrix; Failure; Fatty acid glycerol esters; Foundations; Functional disorder; Future; Galectin 3; General Population; Goals; Human; In Vitro; Individual; Infrastructure; Insulin Resistance; Knowledge; Link; Literature; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Michigan; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organ; Pathogenesis; Play; Process; Proteome; Proteomics; Public Health; Receptor Signaling; Regulation; Research; Research Personnel; Risk; Role; Scientist; Signal Transduction; System; Testing; Therapeutic; Therapeutic Agents; Tissue Engineering; Tissue Transplantation; Tissues; Toxic effect; Transplantation; Tube; Universities; Veterans; Visceral; base; defined contribution; diabetes pathogenesis; experience; experimental study; human model; human tissue; in vivo; innovation; interest; metabolic phenotype; military veteran; mouse model; new therapeutic target; novel; novel therapeutic intervention; patient population; programs; receptor expression; receptor for advanced glycation endproducts; repaired; three dimensional cell culture; tissue resource; transcriptomics; translational potential; transplant model; treatment strategy

PROJECT SUMMARY ABSTRACT Obesity and associated metabolic disease, including type II diabetes, is a public health crisis, the risks of which are elevated in military Veterans. Adipose tissue metabolism is dysregulated in obesity and is a central mediator of diabetes pathogenesis, but underlying mechanisms are not well-defined. The extracellular matrix (ECM) is an understudied component of adipose tissue, and our preliminary data demonstrate that that ECM regulates adipocyte metabolic dysfunction in the context of diabetes. These observations suggest adipose tissue ECM as a novel therapeutic target for diabetes. The scientific goals of this proposal are to define the role of the ECM in regulating adipocyte metabolism, and to develop novel in vitro engineered ECM-based adipose tissues as therapeutic vehicles to manipulate systemic insulin resistance. Our central hypothesis is that in diabetes, Advanced Glycation End-products (AGE)-modified adipose tissue ECM engages in crosstalk with adipocytes, with detrimental effects on tissue and systemic metabolism, contributing to disease pathogenesis. The rationale for this hypothesis is based on extensive literature linking alterations in adipose tissue ECM and metabolism to obesity and diabetes, and preliminary data confirming ECM regulation of adipocyte metabolism and implicating AGE and AGE-receptors in ECM-adipocyte crosstalk. Aim 1 will define the role of AGE in regulating human adipose tissue AGE- receptor signaling balance in diabetes, and perform detailed proteomics analysis to define diabetes-specific alterations in the human adipose tissue ECM proteome. Aim 2 will study the role of AGE and AGE receptors in regulating human adipose tissue metabolism in standard 2D culture and in sophisticated in vitro human 3D- ECM-adipocyte culture models. Aim 3 will study the role of adipose tissue ECM in regulating systemic insulin resistance using an innovative murine ECM-adipocyte transplant model. This project is significant because it will define mechanisms of ECM-adipocyte crosstalk in diabetes, bridging an important knowledge gap and advancing an understanding of ECM control of adipose tissue and systemic metabolism. This project also studies transplant of engineered ECM-based adipose tissue in murine obesity, a novel treatment strategy for diabetes with significant translational potential. The PI of this project Robert O'Rourke, MD, is a VA clinician-scientist with extensive experience in adipose tissue biology and metabolic disease research. This proposal will establish a unique obesity-research program within the VA system.

项目概要摘要 肥胖和相关代谢疾病，包括 II 型糖尿病，是一场公共卫生危机，其风险 在退伍军人中地位较高。脂肪组织代谢在肥胖症中失调，是肥胖的核心 糖尿病发病机制的介质，但其潜在机制尚不明确。细胞外基质 (ECM) 是脂肪组织的一个尚未被研究的成分，我们的初步数据表明 ECM 调节糖尿病背景下的脂肪细胞代谢功能障碍。这些观察结果表明脂肪 组织 ECM 作为糖尿病的新治疗靶点。 该提案的科学目标是明确 ECM 在调节脂肪细胞代谢中的作用，以及 开发新型体​​外工程化的基于 ECM 的脂肪组织作为治疗载体来操纵 全身性胰岛素抵抗。我们的中心假设是，在糖尿病中，晚期糖基化终产物 (AGE) 修饰的脂肪组织 ECM 与脂肪细胞发生串扰，对组织产生有害影响 和全身代谢，促进疾病发病机制。该假设的基本原理是基于 将脂肪组织 ECM 和代谢的改变与肥胖和糖尿病联系起来的大量文献，以及 初步数据证实 ECM 对脂肪细胞代谢的调节并涉及 AGE 和 AGE 受体 ECM-脂肪细胞串扰。目标 1 将定义 AGE 在调节人体脂肪组织中的作用 AGE- 糖尿病中的受体信号平衡，并进行详细的蛋白质组学分析来定义糖尿病特异性 人类脂肪组织 ECM 蛋白质组的改变。目标 2 将研究 AGE 和 AGE 受体在 在标准 2D 培养和复杂的体外人体 3D 培养中调节人体脂肪组织代谢 ECM-脂肪细胞培养模型。目标 3 将研究脂肪组织 ECM 在调节全身胰岛素中的作用 使用创新的小鼠 ECM 脂肪细胞移植模型来抵抗耐药性。这个项目意义重大，因为它 将定义糖尿病中 ECM-脂肪细胞串扰的机制，弥合重要的知识差距和 促进对脂肪组织和全身代谢的 ECM 控制的理解。这个项目还 研究基于 ECM 的工程脂肪组织移植治疗小鼠肥胖症，这是一种新的治疗策略 具有显着转化潜力的糖尿病。 该项目的 PI 医学博士 Robert O'Rourke 是一位 VA 临床医生科学家，在脂肪领域拥有丰富的经验 组织生物学和代谢疾病研究。该提案将建立一个独特的肥胖研究计划 在 VA 系统内。