Extracellular matrix-adipocyte metabolic crosstalk and diabetes

细胞外基质-脂肪细胞代谢串扰与糖尿病

基本信息

批准号：
10472132
负责人：
ROBERT W O'ROURKE
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10472132
关键词：
3-Dimensional Address Adipocytes Adipose tissue Advanced Glycosylation End Products Biology Biomedical Engineering CD18 Antigens Cell Communication Cell Transplantation Cell physiology Cells Chronic Cytoskeleton Data Development Diabetes Mellitus Diabetic mouse Disease Doctor of Philosophy Engineering Extracellular Matrix Fatty acid glycerol esters Functional disorder Goals Human Hydrogels ITGB2 gene In Vitro Infrastructure Insulin Insulin Resistance Integrins Knowledge Link Lipids Literature Mechanics Mediating Mediator Metabolic Metabolic Diseases Metabolic dysfunction Metabolism Modeling Modification Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Organ Pathogenesis Phenotype Play Population Positioning Attribute Public Health Regulation Research Research Personnel Research Support Risk Role Scientist Signal Transduction Stromal Cells Study models System Testing Tissues Toxic effect Transplantation Tube Xenograft Model cellular engineering clinically relevant diabetes pathogenesis experience experimental study human tissue in vivo insight military veteran mouse model new therapeutic target novel programs repaired response rho translational potential transplant model treatment strategy

项目摘要

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 and identify Advanced Glycation End- products (AGE) modification of the ECM as a mechanisms of adipose tissue dysfunction in 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 and AGE in regulating adipocyte metabolism, and to develop novel adipose tissue-based vehicles to manipulate systemic insulin resistance in vivo. Our central hypothesis is that in diabetes, adipose tissue ECM regulates adipocyte cellular metabolism via an AGE-integrin-cytoskeleton signaling axis triggered by increased matrix stiffness in DM, and that manipulation of matrix stiffness can be exploited to modulate adipocyte cellular metabolism and the effects of ASC on systemic insulin resistance. The rationale for this hypothesis is based on extensive literature linking alterations in adipose tissue ECM and metabolism to obesity and diabetes, and our preliminary data confirming ECM regulation of adipocyte metabolism and implicating AGE- mediated regulation of the adipocyte cytoskeleton in ECM-adipocyte crosstalk. Aim 1 will define the role of AGE-integrin-cytoskeleton signaling in regulating human adipose tissue dysfunction in vitro in the context of diabetes in a human ECM-adipocyte culture system. Aim 2 will study the role of AGE in regulating human adipose tissue metabolism in an in vitro human 3D-adipocyte hydrogel culture model that permits manipulation of matrix mechanics. Aim 3 will study the role of adipose stromal cells and matrix in regulating systemic metabolism using a murine xenograft transplant model in which human adipose tissue stromal cells are transplanted into mice in engineered hydrogel vehicles to ameliorate systemic insulin resistance. 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 human adipose tissue stromal cells delivered in engineered artificial matrix in murine obesity addressing an important knowledge gap that will study the role of human cells in regulatinging system metabolism, and serving as a first step towards development of novel treatment strategies for diabetes with significant translational potential. The PI, Robert O’Rourke, MD, is a VA clinician-scientist with extensive experience in adipose tissue and metabolic disease research. Our research team includes co-investigators Andrew Putnam, PhD, a bioengineer with expertise in matrix-cell engineering, and Carey Lumeng, MD, PhD, an adipose tissue biologist with expertise in murine models of obesity. This proposal extends an already unique, robust obesity-research program within the VA system established by the PI that has been in place for nearly a decade. This diverse team and infrastructure maximizes the likelihood of this proposal generating novel, clinically relevant findings.

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，其风险退伍军人的脂肪组织代谢失调，是肥胖的一个核心。细胞外基质是糖尿病发病机制的介质，但其潜在机制尚不明确。 (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并识别高级糖基化终末- ECM 产物（AGE）修饰作为糖尿病脂肪组织功能障碍的机制。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 和 AGE 在调节脂肪细胞中的作用代谢，并开发新型基于脂肪组织的载体来操纵全身胰岛素抵抗我们的中心假设是，在糖尿病中，脂肪组织 ECM 调节脂肪细胞代谢。通过 DM 中基质硬度增加触发的 AGE-整合素-细胞骨架信号轴，并且基质硬度的操纵可用于调节脂肪细胞的代谢及其影响 ASC 关于全身胰岛素抵抗的理论基础是基于大量文献链接。脂肪组织 ECM 和代谢的改变导致肥胖和糖尿病，我们的初步数据证实 ECM 对脂肪细胞代谢的调节以及 AGE 介导的脂肪细胞调节细胞骨架在 ECM-脂肪细胞串扰中的作用目标 1 将定义 AGE-整合素-细胞骨架信号传导在细胞骨架中的作用。在糖尿病背景下体外调节人类 ECM 脂肪细胞中的人类脂肪组织功能障碍目标 2 将在体外研究 AGE 在调节人体脂肪组织代谢中的作用。 Aim 3 将研究允许操纵基质力学的人体 3D 脂肪细胞水凝胶培养模型。脂肪基质细胞和基质在利用鼠异种移植物调节全身代谢中的作用将人类脂肪组织基质细胞移植到小鼠体内的移植模型改善全身胰岛素抵抗的水凝胶载体该项目意义重大，因为它将定义。糖尿病中 ECM-脂肪细胞串扰的机制，弥合了重要的知识差距并推进了了解 ECM 对脂肪组织和全身代谢的控制。该项目还进行移植研究。人类脂肪组织基质细胞在小鼠肥胖症中的工程人工基质中传递，解决了重要的知识缺口将研究人体细胞在调节系统代谢中的作用，以及这是开发糖尿病新治疗策略的第一步，具有显着的效果翻译潜力。 PI 罗伯特·奥罗克 (Robert O’Rourke) 医学博士是一位 VA 临床医生科学家，在脂肪组织和我们的研究团队包括生物工程师 Andrew Putnam 博士。拥有基质细胞工程方面的专业知识，Carey Lumeng 博士是一位脂肪组织生物学家，该提案扩展了本已独特、稳健的肥胖研究。 PI 建立的 VA 系统内的计划已经实施了近十年。团队和基础设施最大限度地提高了该提案产生新颖的、临床相关发现的可能性。