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降低了约3000万人中大多数人的活动性和生活质量 美国糖尿病患者，导致这些个人和社会的巨大经济负担。任何新 增强糖尿病患者肌腱功能的方法受到了对糖尿病的认识不足的阻碍。 肌腱生物力学特性受损的潜在病因。重要的是，各种血清因子 在糖尿病患者肌腱并发症的发展中的作用尚不清楚。我们 多学科研究小组假设，血清晚期糖基化终产物（AGEs）增加， 随后AGEs（AGEs）受体激活，是驱动肌腱的主要机制 糖尿病并发症。具体而言，激活的tenocyte损害肌腱细胞的功能，导致损失的， 胶原纤维组织和随后的生物力学功能损伤。AGEs聚集在 糖尿病患者血清。我们的初步细胞培养工作表明，用 AGEs不能形成胶原交联，对肌腱ECM维持的关键方面产生不利影响。 我们还发现AGEs促进有利于肌腱ECM降解的环境。利用载人 受试者，我们证明血清AGE浓度的增加与肌腱功能下降有关， 生物力学性质（例如，模数）。血清AGEs可与炎症因子相互作用，促进炎症反应， 氧化应激，但这种连接到肌腱ECM组织和生物力学功能的变化 尚未确定减值。本课题的目的是：1）阐明血清AGEs及其活化在糖尿病发病中的作用， 在促进肌腱ECM破坏和生物力学性能的损害和2） 确定血清AGEs与体内肌腱生物力学特性和体内 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 功能和减少这种具有挑战性的临床条件的经济和社会负担。使用小鼠模型 我们将通过诱导型β 2-淀粉样蛋白缺失和2型糖尿病模型， 血清AGEs升高对肌腱ECM组织和生物力学功能的影响， 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、体内肌腱模量和肌腱ECM MRI指标之间的关系 organization.我们希望这项工作能够表明，AGEs通过β信号传导是一个主要的机制， 糖尿病患者肌腱细胞外基质的变化以及随后的生物力学功能下降。 明确血清AGEs和β-淀粉样蛋白信号在糖尿病肌腱表型形成中的作用， 提供了一种途径来评估新的治疗方法，以减少肌腱并发症的影响， 糖尿病患者。我们的建议符合NIAMS的使命，即制定肌腱相关的治疗策略。 受伤我们的项目涉及NIDDK的使命，即制定预防和治疗并发症的策略。 糖尿病