Extracellular matrix-adipocyte metabolic crosstalk and diabetes

项目摘要 肥胖和相关的代谢疾病，包括II型糖尿病，是一种公共卫生危机，其风险 在退伍军人中的比例很高。脂肪组织代谢在肥胖症中失调，并且是肥胖症的核心代谢途径。 糖尿病发病机制的介质，但根本的机制是没有明确的。细胞外基质 (ECM)是脂肪组织中一种未充分研究的成分，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作为糖尿病治疗的新靶点。 该提案的科学目标是确定ECM在调节脂肪细胞代谢中的作用， 开发新型体外工程ECM脂肪组织作为治疗载体， 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，有助于疾病的发病机制。这一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， 初步数据证实ECM调节脂肪细胞代谢并涉及AGE和AGE受体 ECM-脂肪细胞串扰。目的1将明确AGE在调节人脂肪组织AGE中的作用， 受体信号平衡，并进行详细的蛋白质组学分析，以确定糖尿病特异性 人类脂肪组织ECM蛋白质组的改变。目的2：研究AGE及其受体在肿瘤发生发展中的作用。 在标准2D培养和复杂的体外人3D培养中调节人脂肪组织代谢， ECM-脂肪细胞培养模型。目的3研究脂肪组织细胞外基质在调节胰岛素分泌中的作用 使用创新的鼠ECM-脂肪细胞移植模型研究抗肿瘤药物的耐药性。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， 促进对脂肪组织和全身代谢的ECM控制的理解。该项目还 研究了小鼠肥胖症中基于ECM的工程脂肪组织的移植，这是一种新的治疗策略， 糖尿病具有显著的转化潜力。 该项目的PI Robert O 'Rourke，MD，是一名VA临床医生-科学家，在脂肪治疗方面具有丰富的经验。 组织生物学和代谢疾病研究。这项提案将建立一个独特的肥胖研究计划 在VA系统中。

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.