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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：
10803535
负责人：
Erica L Clinkenbeard
金额：
$ 39.13万
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：
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/10803535
关键词：
Acetyltransferase Address Adenine Affect American Automobile Driving Award Biopsy Bone Diseases Bone Formation Inhibition Bone Marrow Bone Resorption Calcium Calvaria Catabolism Cell Differentiation process Cells Chronic Chronic Kidney Failure Coupling DNA Development Diet 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 Link Mediating Metabolism Minerals Mission Modeling Morbidity - disease rate Morphology Mus Osteoblasts Osteoclasts Osteogenesis Osteoporosis Outcome Pathogenicity Pathology Patients 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 bone bone fragility bone loss bone turnover cell growth comorbidity comparison control fracture risk improved in vivo innovation inorganic phosphate iron deficiency loss of function mutation mineralization mortality new therapeutic target novel novel therapeutic intervention novel therapeutics osteoblast differentiation overexpression pharmacologic 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.

项目概要/摘要：骨脆性增加骨折风险是骨矿物质和骨骼疾病的定义成分之一，慢性肾病（CKD-MBD）。CKD患者的骨稳态失调与以下因素显著相关：发病率和死亡率，因为CKD患者骨折后死亡率更高。此外，本发明的目的是，不能维持正常的骨稳态有助于升高的循环钙和磷，血管钙化的发展。腺嘌呤饮食诱导的小鼠肾衰竭模型表现出与CKD患者骨活检平行的致病性骨改变，包括多孔性和破骨细胞升高 number.这些组织学特征与缺铁性贫血的发生有关， CKD期间经常发生。然而，破坏铁处理对骨稳态的直接影响肾功能衰竭的原因尚不清楚。以前的研究发现，缺铁会使骨形成变钝，成骨细胞和啮齿类动物喂养缺铁饮食。最近的研究发现，缺铁改变细胞多胺合成，最终降低精胺和亚精胺含量。精胺和已经发现亚精胺对于成骨细胞分化和功能是重要的。与对照相比，还观察到CKD患者精胺水平降低。的统一该建议的假设是CKD-MBD中成骨细胞分化受损，病理生理学是由缺铁减少多胺合成介导的。我们把这条新奇的大道斯蒂芬一世的研究有两个具体目标。Katz早期研究者研究补助金。在目标1中，我们将检验缺铁介导的精胺减少抑制成骨细胞的假说，分化这将通过评估精胺补充在缺铁在体外和体内的条件下。以前的研究表明，缺铁可能钝化精胺通过还原精胺合酶进行转化。因此，我们还将研究骨保护性转基因 CKD缺铁时精胺合酶的上调。最后，为了确定这些小分子改变基因表达，我们将进行表观遗传测序研究，多胺被认为与DNA可及性的变化有关。在目标2中，我们将测试 CKD缺铁在细胞和系统水平上促进多胺催化的假说。在患者研究中，发现CKD血清与对照相比具有升高的精胺氧化酶活性。此外，缺铁可增加分解代谢精胺的N-乙酰转移酶蛋白水平。我们将在CKD缺铁期间进行遗传和药理学抑制，以解决这些新的问题.这些研究的完成将大大提高我们对骨稳态的理解， CKD的背景。我们的研究也将在干预方面具有重要的治疗意义铁缺乏症和慢性肾脏病-心肌病