Extracellular matrix-adipocyte metabolic crosstalk and diabetes

项目总结摘要 肥胖和相关的代谢性疾病，包括II型糖尿病，是一种公共健康危机，其风险 在退伍军人中得到提升。肥胖患者脂肪组织代谢失调，是肥胖的中枢 糖尿病发病机制的介体，但其潜在机制还不是很清楚。细胞外基质 细胞外基质(ECM)是脂肪组织中一种研究不足的成分，我们的初步数据表明，ECM 在糖尿病的情况下调节脂肪细胞代谢功能障碍。这些观察结果表明 组织细胞外基质作为糖尿病治疗的新靶点。 这项建议的科学目标是确定细胞外基质在调节脂肪细胞代谢中的作用，以及 开发新型体外工程化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，在糖尿病患者中，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，促成疾病的发病机制。这一假设的基本原理是基于 大量文献将脂肪组织ECM和新陈代谢的改变与肥胖和糖尿病联系起来，以及 初步数据证实细胞外基质对脂肪细胞代谢的调控及与AGE及其受体的关系 在ECM中--脂肪细胞的串音。目标1将定义年龄在调节人类脂肪组织年龄中的作用- 糖尿病中的受体信号平衡，并进行详细的蛋白质组学分析以确定糖尿病特异性 人类脂肪组织细胞外基质蛋白质组的变化。目标2将研究AGE和AGE受体在 在标准的2D培养和复杂的体外人类3D培养中调节人类脂肪组织的代谢- 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全身性胰岛素中的作用 使用一种创新的小鼠细胞外基质-脂肪细胞移植模型进行耐药性研究。这个项目意义重大，因为它 将确定糖尿病患者细胞外基质-脂肪细胞串扰的机制，弥合重要的知识鸿沟和 增进对细胞外基质对脂肪组织和全身代谢的控制的认识。这个项目还 以工程ECM为基础的脂肪组织移植治疗小鼠肥胖的研究--一种新的治疗策略 具有显著翻译潜力的糖尿病。 这个项目的PI是罗伯特·奥鲁尔克医学博士，他是一名退伍军人管理局的临床医生和科学家，在脂肪方面有丰富的经验 组织生物学和代谢性疾病研究。这项提案将建立一个独特的肥胖研究项目 在退伍军人管理局系统内。

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.