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Pathogenesis of compromised bone quality and mechanics in chronic kidney disease.

慢性肾脏病中骨质量和力学受损的发病机制。

基本信息

批准号：
9751842
负责人：
Matthew R Allen
金额：
$ 43.13万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-05 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751842
关键词：
Acetylcysteine Advanced Glycosylation End Products American Animals Archives Biochemical Markers Biological Assay Biopsy Blood Bone Marrow Bone Marrow Cells Bone structure Chronic Kidney Failure Clinical Collagen Collagen Type I Data Diagnostic radiologic examination Dialysis patients Diet Discrimination Disease Extracellular Matrix Fracture Gene Expression Generations Geometry Goals High Pressure Liquid Chromatography Human Impairment In Vitro Individual Intestinal Absorption Kidney Diseases Measures Mechanics Mesenchymal Stem Cells Modeling Morphology Osteoblasts Outcome Pathogenesis Patients Peripheral Pharmacotherapy Play Positioning Attribute Production Property Proteins Rattus Recording of previous events Regression Analysis Resolution Rodent Role Serum Severity of illness Signal Pathway Small Interfering RNA Specimen Testing Time Tissues Translating Universities Vertebral column Work X-Ray Computed Tomography absorption aged base bone bone age bone imaging bone quality cohort cortical bone crosslink density experimental study fracture risk high risk improved in vivo mechanical properties microCT mineralization morphometry negative affect non-diabetic novel novel strategies osteoblast differentiation pre-clinical receptor expression receptor for advanced glycation endproducts sevelamer skeletal skeletal disorder substantia spongiosa

项目摘要

Reduced bone quality is a key determinant of skeletal fragility in CKD, but the details of this effect are not well defined. Non-enzymatic collagen crosslinks (formed via advanced glycation end-products, AGEs) negatively affect bone mechanical properties and AGEs are elevated in the blood and bone of patients and animals with advanced CKD. We propose that skeletal accumulation of AGE collagen cross links may play a critical role in CKD skeletal fragility and reducing AGEs may represent a novel approach to reduce fracture risk in CKD patients. The overall goal of this study is to test the hypothesis that skeletal AGEs induce negative mechanical and cellular effects in CKD and that circulating AGE levels can help in CKD patient fracture discrimination. This goal will be accomplished through a combination of pre-clinical experiments using our established model of progressive CKD (the Cy/+ rat), novel human biopsy assays, and state-of-the art bone imaging with second generation high resolution peripheral quantitative computed tomography. The multi-university interdisciplinary team is perfectly positioned to undertake this translational work based on their clinical and preclinical expertise in bone, collagen/AGEs, mechanics, and CKD. In Aim 1 we will determine if AGE- lowering drug treatments that reduce endogenous AGE production or gastrointestinal absorption improve the skeletal properties of animals with progressive CKD. In Aim 2 we will assess the effect of disease severity on human bone AGE accumulation and its relationship to mechanical properties by measuring bone AGE levels and mechanical properties from transiliac crest bone biopsies from patients with CKD. In Aim 3, we will quantify the ability of AGE levels to improve fracture discrimination in CKD patients. In Aim 4, we will determine if AGE accumulation in the bone extracellular matrix impairs bone marrow derived osteoblast differentiation, function and AGE receptor expression. The current proposal will build on our body of work characterizing abnormal bone quality in patients with CKD by studying how agents that modulate AGEs through different mechanisms alter skeletal accumulation of AGEs and bone mechanical properties in animals and humans. If these studies show efficacy in benefiting skeletal mechanical properties, these treatments could be rapidly translated into the clinical setting.

骨质量降低是CKD患者骨骼脆弱性的关键决定因素，但其细节效果并不明确。非酶胶原交联（通过晚期糖化形成终产物（AGEs）对骨机械性能有负面影响，晚期CKD患者和动物的血液和骨骼。我们建议骨骼 AGE胶原交联的积累可能在CKD骨骼脆性中起关键作用，降低AGEs可能是降低CKD患者骨折风险的一种新方法。的本研究的总体目标是检验骨骼AGEs诱导负性慢性肾病的机械和细胞效应，循环AGE水平可以帮助慢性肾病患者骨折鉴别这一目标将通过结合临床前使用我们建立的进行性CKD模型（Cy/+大鼠）进行的实验，活检分析和第二代高分辨率的最先进骨成像外周定量计算机断层扫描。多所大学的跨学科团队是完全能够根据他们的临床和临床前研究成果，骨、胶原/AGEs、力学和CKD方面的专业知识。在目标1中，我们将确定年龄- 降低内源性AGE产生或胃肠道吸收的药物治疗改善患有进行性CKD的动物的骨骼特性。在目标2中，我们将评估疾病严重程度对人骨AGE蓄积影响及其与机械强度的关系通过测量来自髂嵴骨的骨AGE水平和机械性能， CKD患者的活检。在目标3中，我们将量化AGE水平改善 CKD患者的骨折识别。在目标4中，我们将确定是否存在AGE蓄积，骨细胞外基质损害骨髓来源的成骨细胞分化、功能和 AGE受体表达。目前的建议将建立在我们的工作基础上，通过研究调节AGEs的药物如何调节CKD患者的骨质量异常通过不同的机制改变AGEs在骨骼中的积聚和骨机械强度动物和人类的特性。如果这些研究显示，机械性能，这些治疗可以迅速转化为临床环境。