Role of serum advanced glycation end-products in altering tendon properties with diabetes

血清晚期糖基化终末产物在改变糖尿病肌腱特性中的作用

• 批准号: 10737036
• 负责人: Chad Clayton Carroll
• 金额: $ 64.23万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737036
• 关键词: Address; Advanced Glycosylation End Products; Affect; American; Automobile Driving; Biomechanics; Blood Glucose; Bovine Serum Albumin; Cell Culture Techniques; Cell Survival; Cells; Chronic; Clinical; Collagen; Collagen Fiber; Collagen Fibril; Complications of Diabetes Mellitus; Critical Pathways; Data; Deterioration; Development; Diabetes Mellitus; Diabetic mouse; Economic Burden; Economic Conditions; Environment; Etiology; Extracellular Matrix; Extracellular Matrix Degradation; Food; Frequencies; Genes; Genetic; Glycosylated hemoglobin A; Goals; Health; Homeostasis; Human; Hyperglycemia; Impairment; Individual; Inflammation; Injury; Intake; Interdisciplinary Study; Kidney; Knock-out; Knowledge; Magnetic Resonance Imaging; Maintenance; Mechanics; Mediating; Mediator; Methodology; Mission; Modeling; Modification; Modulus; Morphology; Mus; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pathology; Patients; Persons; Phenotype; Play; Prevention strategy; Process; Property; Quality of life; Receptor Activation; Research; Risk; Rodent; Role; Serum; Shapes; Signal Transduction; Societies; Study of serum; Tendon Injuries; Tendon structure; Testing; Therapeutic; Work; crosslink; db/db mouse; diabetic; dimer; glycolaldehyde; human subject; imaging modality; improved; in vivo; inhibitor; loss of function; mouse model; non-diabetic; novel; novel strategies; prevent; receptor for advanced glycation endproducts; social; tendon development; treatment strategy; ultrasound; western diet

PROJECT SUMMARY Impaired tendon biomechanical function reduces mobility and quality of life for the majority of the ~30 million Americans with diabetes, resulting in a substantial economic burden to these individuals and society. Any new approach to enhancing tendon function in people with diabetes is hindered by a poor understanding of the underlying etiology of impaired tendon biomechanical properties. Critically, the role that various serum factors play in the development of tendon complications in individuals with diabetes remains unclear. Our multidisciplinary research team hypothesizes that increased serum advanced glycation end-products (AGEs), with subsequent activation of receptors for AGEs (RAGE), is a principal mechanism driving tendon complications with diabetes. Specifically, activation of RAGE impairs tenocyte function resulting in loss of collagen fibril organization and subsequent impairment of biomechanical function. AGEs accumulate in the serum of patients with diabetes. Our preliminary cell culture work shows that treating tendon-derived cells with AGEs, which cannot form collagen crosslinks, adversely affects critical aspects of tendon ECM maintenance. We have also found that AGEs promote an environment favoring tendon ECM degradation. Utilizing human subjects, we demonstrate that increasing serum AGE concentrations are associated with declining tendon biomechanical properties (e.g., modulus). Serum AGEs can interact with RAGE to promote inflammation and oxidative stress, but such a connection to changes in tendon ECM organization and biomechanical function impairment has not been established. This project aims to 1) delineate the role of serum AGEs and activation of RAGE in promoting tendon ECM disorganization and impairment of biomechanical properties and 2) determine the relationship of serum AGEs to in vivo tendon biomechanical properties and in vivo indicators of tendon collagen fibril organization. Filling these gaps will promote new approaches for improving tendon function and reducing this challenging clinical condition's economic and social burden. Using a mouse model with an inducible RAGE deletion and a model of type 2 diabetes, we will assess the effects of chronically elevated serum AGEs on tendon ECM organization and biomechanical function and the involvement of RAGE in this process. We will use novel ultrasound and magnetic resonance imaging (MRI) methods to determine the relationships between serum AGE concentrations, in vivo tendon modulus, and MRI indicators of tendon ECM organization. We expect this work to show that AGEs via RAGE signaling are a principal mechanism driving changes in tendon ECM and subsequent reduction in biomechanical function in patients with diabetes. Defining the role of serum AGEs and RAGE signaling in the development of the diabetic tendon phenotype will provide an avenue to evaluate novel treatment approaches to reduce the impact of tendon complications in patients with diabetes. Our proposal fits NIAMS's mission of developing treatment strategies for tendon-related injuries. Our project addresses NIDDK’s mission of developing strategies to prevent and treat complications of diabetes.

项目摘要 肌腱生物力学功能受损可降低约3000万的大多数人的活动能力和生活质量 患有糖尿病的美国人，为这些个人和社会带来了实质性的经济伯恩。任何新的 对糖尿病患者增强肌腱功能的方法受到了对 肌腱生物力学特性受损的基本病因。至关重要的是各种血清因素的作用 糖尿病患者肌腱并发症的发育尚不清楚。我们的 多学科研究团队假设增加了血清高级糖基化终产物（年龄）， 随后激活年龄的接收器（RAGE）是一种主要机制驱动肌腱 糖尿病并发症。具体而言，愤怒的激活会损害替纳cy型功能，导致损失 胶原原纤维组织以及随后的生物力学功能受损。年龄在 糖尿病患者的血清。我们的初步细胞培养工作表明，用 不能形成胶原蛋白交联的年龄会对肌腱ECM维护的关键方面产生不利影响。 我们还发现，年龄促进了有利于肌腱ECM降解的环境。利用人类 受试者，我们证明血清年龄浓度的增加与肌腱下降有关 生物力学特性（例如模量）。血清年龄可以与愤怒相互作用以促进注射和 氧化应激，但与肌腱ECM组织和生物力学功能变化的这种联系 尚未确定损害。该项目的目的是1）描述血清年龄和激活的作用 促进肌腱ECM混乱和生物力学特性损害的愤怒和2） 确定血清年龄与体内肌腱生物力学特性和体内指标的关系 肌腱胶原纤维组织。填补这些空白将促进改善肌腱的新方法 功能并减少这种挑战临床状况的经济和社会伯恩。使用鼠标模型 通过诱导的愤怒缺失和2型糖尿病模型，我们将评估长期的影响 肌腱ECM组织和生物力学功能的血清年龄高高以及愤怒的参与 在此过程中。我们将使用新颖的超声和磁共振成像（MRI）方法来确定 血清年龄浓度，体内肌腱模量和肌腱ECM的MRI指标之间的关系 组织。我们希望这项工作表明，通过愤怒信号传导年龄是一种主要机制驱动 肌腱ECM的变化以及随后糖尿病患者生物力学功能的降低。 定义血清年龄和愤怒信号在糖尿病肌腱表型发育中的作用 提供了一种评估新型治疗方法的途径，以减少肌腱并发症的影响 糖尿病患者。我们的建议符合Niams制定与肌腱相关的治疗策略的使命 受伤。我们的项目解决了NIDDK制定策略以预防和治疗并发症的使命 糖尿病。