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.

项目总结 肌腱生物力学功能受损降低了约3000万人的活动能力和生活质量 美国人患有糖尿病，给这些个人和社会带来了巨大的经济负担。任何新的 糖尿病患者增强肌腱功能的方法因对肌腱功能认识不足而受阻 肌腱生物力学性能受损的潜在病因。关键是，各种血清因子的作用 糖尿病患者肌腱并发症的发病机制尚不清楚。我们的 多学科研究团队假设，血清晚期糖基化终产物(AGEs)增加， 随后激活的AGEs受体(RAGE)是驱动肌腱的主要机制 糖尿病并发症。具体地说，RAGE的激活损害了腱细胞的功能，导致了 胶原原纤维的组织和随后的生物力学功能损害。岁月积聚在 糖尿病患者的血清。我们的初步细胞培养工作表明，用 AGEs不能形成胶原交联物，对肌腱ECM维持的关键方面产生不利影响。 我们还发现，AGE促进了有利于肌腱ECM降解的环境。利用人 研究对象，我们证明血清AGE浓度的增加与肌腱的下降有关。 生物力学性能(例如，模数)。血清AGEs可与RAGE相互作用，促进炎症和 氧化应激，但这种联系与肌腱ECM组织和生物力学功能的变化有关 减值尚未确定。这个项目的目的是1)描述血清AGEs和激活的作用 RAGE在促进肌腱细胞外基质解离和生物力学性能损伤中的作用 测定血清AGEs与体内肌腱生物力学性能及体内指标的关系 肌腱胶原原纤维组织。填补这些空白将促进改善肌腱的新方法 功能，并减轻这一具有挑战性的临床条件下的经济和社会负担。使用鼠标模型 通过可诱导的RAGE缺失和2型糖尿病模型，我们将评估慢性 血清AGEs升高对肌腱ECM组织和生物力学功能的影响及其与RAGE的关系 在这个过程中。我们将使用新的超声和磁共振成像(MRI)方法来确定 血清AGE浓度、活体肌腱弹性与肌腱细胞外基质MRI指标的关系 组织。我们希望这项研究表明，年龄通过RAGE信号是一个主要的驱动机制 糖尿病患者肌腱细胞外基质的变化和随后的生物力学功能降低。 明确血清AGEs和RAGE信号在糖尿病肌腱表型发展中的作用将 为评估新的治疗方法以减少肌腱并发症的影响提供了途径 糖尿病患者。我们的建议符合NIAMS制定肌腱相关治疗策略的使命 受伤。我们的项目满足了NIDDK制定预防和治疗并发症的战略的使命 糖尿病。