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：
10540418
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/10540418
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.

项目摘要/摘要：骨骼脆弱性增加断裂风险是矿物质和骨疾病的定义成分之一慢性肾脏疾病（CKD-MBD）。 CKD中的骨稳态失调与作为骨折的CKD患者的发病率和死亡率表现出更高的死亡率。此外，无法维持正常的骨骼平衡会导致循环钙和磷的升高以及血管钙化的发展。小鼠腺嘌呤 - 抑制诱导的肾衰竭模型与CKD患者骨骼活检平行的致病骨变化，包括孔隙率和破骨细胞升高数字。这些组织学特征与铁缺乏贫血的发展一起出现 CKD期间频繁出现。但是，破坏铁处理对骨骼体内平衡的直接影响在肾衰竭期间仍不清楚。先前的研究发现铁缺乏钝性骨形成骨骼瓦尔瓦里亚成骨细胞和啮齿动物中喂养铁不足的饮食。最近的研究发现铁缺乏症改变细胞多胺合成最终降低精子和精子含量。都是精子和已经发现精子定为成骨细胞分化和功能有趣的是患者很重要与对照组相比，还观察到使用CKD降低了精子水平。统一该提案的假设是成骨细胞的分化，在CKD-MBD中受损，关键部分病理生理学是由铁缺乏症降低的多胺合成介导的。我们解决这一新颖的途径在这个Stephen I. Katz早期研究者研究赠款中，具有两个具体目标的研究。在AIM 1中，我们将测试以下假设：铁缺陷介导的杀精子抑制成骨细胞分化。这将通过评估铁缺乏期间的补充精子来实现体外和体内的条件。先前的研究表明铁缺乏可能会钝化精子通过减少精子合酶的转化。因此，我们还将检查骨保护性转基因 CKD铁缺乏期间，精子合酶的上调。最后，确定这些小的分子改变基因表达，我们将进行表观遗传测序研究，既是铁缺乏症，又已经假定多胺与DNA可及性的变化有关。在AIM 2中，我们将测试假设CKD的铁缺乏促进了细胞和全身水平的多胺分解代谢。在患者研究，与对照组相比，发现CKD血清具有升高的精子氧化酶活性。另外，铁缺乏可以增加分解精子分解代谢的N-乙酰基转移酶蛋白水平。我们将在CKD的铁缺乏症过程中承担遗传和药理抑制以解决这些新颖问题。这些研究的完成将显着增强我们对骨骼体内平衡的理解 CKD的上下文。我们的研究还将在干预方面具有重要的治疗意义用于铁缺乏和CKD-MBD。