权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

骨质量降低是慢性肾脏病骨骼脆性的关键决定因素，但这一细节效果没有很好地定义。非酶胶原交联物(通过高级糖基化形成最终产品，年龄)对骨机械性能产生负面影响，年龄在晚期CKD患者和动物的血液和骨骼。我们认为骨骼 AGE胶原交联物的积累可能在CKD骨骼脆性和降低年龄可能是降低CKD患者骨折风险的一种新方法。这个这项研究的总体目标是检验骨龄导致负面影响的假设慢性肾脏病的机械和细胞效应以及循环年龄水平对慢性肾脏病患者的帮助骨折歧视。这一目标将通过临床前利用我们建立的进展性CKD模型(Cy/+大鼠)进行的实验，新人类活组织检查和最先进的第二代高分辨率骨骼成像外周定量计算机断层扫描。多所大学的跨学科团队是基于他们的临床和临床前工作，完全有能力承担这项翻译工作在骨骼、胶原蛋白/AGEs、力学和慢性肾脏病方面的专业知识。在目标1中，我们将确定年龄是否- 减少内源性AGE产生或胃肠道吸收的药物治疗改善进展性慢性肾脏病动物的骨骼性能。在目标2，我们将评估疾病严重程度对人体骨龄积累的影响及其与力学的关系测量横断骨的骨龄水平和力学性能的特性 CKD患者的活组织检查。在目标3中，我们将量化年龄水平提高的能力慢性肾脏病患者的骨折辨别。在目标4中，我们将确定年龄是否在骨细胞外基质损害骨髓源性成骨细胞的分化、功能和 AGE受体的表达。目前的提案将建立在我们的工作主体的基础上，通过研究调节年龄的因素对慢性肾脏病患者骨质量异常的影响通过不同的机制改变骨骼堆积的AGEs和骨力学动物和人类的特性。如果这些研究显示对骨骼有益机械性能，这些治疗方法可以迅速转化为临床环境。