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Role of disrupted polyamine synthesis during CKD-MBD related bone loss

多胺合成中断在 CKD-MBD 相关骨质流失过程中的作用

基本信息

批准号：
10333851
负责人：
Erica L Clinkenbeard
金额：
$ 40.21万
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：
2021
资助国家：
美国
起止时间：
2021-12-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10333851
关键词：
Acetyltransferase Address Adenine Affect American Attenuated Automobile Driving Award Biopsy Bone Diseases Bone Marrow Bone Resorption Calcium Calvaria Catabolism Cells Chronic Chronic Kidney Failure Coupling DNA Development Diet Differentiation and Growth Disease Enzymes Epigenetic Process Exhibits Foundations Fracture Functional disorder Gene Expression General Population Genetic Hip Fractures Histologic Homeostasis Impairment In Vitro Intervention Iron Iron deficiency anemia Kidney Failure Knowledge Lead Link Mediating Metabolism Minerals Mission Modeling Morbidity - disease rate Morphology Mus Osteoblasts Osteoclasts Osteogenesis Osteoporosis Outcome Pathogenicity Pathology Patients Pharmacology Phosphorus Polyamine Catabolism Polyamines Porosity Production Proteins Putrescine Regimen Renal function Reporting Research Research Personnel Research Project Grants Rodent Role Serum Snyder-Robinson syndrome Spermidine Spermine Spermine Synthase Supplementation Testing Therapeutic Transferase Transgenic Organisms Up-Regulation Vascular calcification Work base bone bone fragility bone loss bone turnover calcium phosphate cell growth comorbidity fracture risk improved in vivo innovation iron deficiency loss of function mutation mineralization mortality new therapeutic target novel novel therapeutic intervention novel therapeutics osteoblast differentiation polyamine oxidase preservation protective effect small molecule stem cells translational applications

项目摘要

Project Summary/Abstract: Bone fragility increasing fracture risk is one of the defining components of mineral and bone disorder of chronic kidney disease (CKD-MBD). Dysregulated bone homeostasis in CKD is significantly linked with morbidity and mortality as patients with CKD that sustain a fracture exhibit higher mortality rates. Additionally, inability to maintain normal bone homeostasis contributes to elevated circulating calcium and phosphorus and development of vascular calcifications. The adenine-diet induced model of renal failure in mice exhibit pathogenic bone alterations parallel to CKD patient bone biopsies including porosity and elevated osteoclasts number. These histological features occur in conjunction with development of iron deficiency anemia, a frequent occurrence during CKD. However, the direct effects of disrupted iron handling on bone homeostasis during renal failure remain unclear. Previous studies have found iron deficiency blunts bone formation both in calvaria osteoblasts and in rodents fed an iron deficient diet. Recent studies have found that iron deficiency alters cellular polyamine synthesis ultimately reducing spermine and spermidine content. Both spermine and spermidine have been found to be important for osteoblast differentiation and function Interestingly, patients with CKD have also been observed to have reduced spermine levels compared to controls. The unifying hypothesis of this proposal is osteoblast differentiation is impaired in CKD-MBD and critical portions of this pathophysiology are mediated by iron deficiency reduced polyamine synthesis. We address this novel avenue of research with two specific aims in this Stephen I. Katz Early Stage Investigator Research Grant. In Aim 1, we will test the hypothesis that iron-deficiency mediated reduction in spermine inhibits osteoblast differentiation. This will be accomplished by assessing spermine supplementation during iron deficiency conditions both in vitro and in vivo. Previous studies indicate that iron deficiency may blunt spermine conversion by reducing spermine synthase. Thus, we will also examine the bone protective transgenic upregulation of spermine synthase during iron deficiency of CKD. Finally, to determine how these small molecules alter gene expression, we will undertake epigenetic sequencing studies as both iron deficiency and polyamines have been postulated to be involved in changes in DNA accessibility. In Aim 2 we will test the hypothesis that iron deficiency of CKD promotes polyamine catabolism at the cellular and systemic level. In patient studies, CKD serum is found to have elevated spermine oxidase activity compared to controls. Additionally, iron deficiency can increase N-acetyltransferase protein levels that catabolize spermine. We will undertake genetic and pharmacological inhibition of during iron deficiency of CKD to address these novel questions. Completion of these studies will significantly enhance our understanding of bone homeostasis in the context of CKD. Our studies will also have important therapeutic implications in regards to interventions for iron deficiency and CKD-MBD.

项目总结/文摘: