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:
- 金额:$ 40.21万
- 依托单位:
- 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:
- 关键词:AcetyltransferaseAddressAdenineAffectAmericanAttenuatedAutomobile DrivingAwardBiopsyBone DiseasesBone MarrowBone ResorptionCalciumCalvariaCatabolismCellsChronicChronic Kidney FailureCouplingDNADevelopmentDietDifferentiation and GrowthDiseaseEnzymesEpigenetic ProcessExhibitsFoundationsFractureFunctional disorderGene ExpressionGeneral PopulationGeneticHip FracturesHistologicHomeostasisImpairmentIn VitroInterventionIronIron deficiency anemiaKidney FailureKnowledgeLeadLinkMediatingMetabolismMineralsMissionModelingMorbidity - disease rateMorphologyMusOsteoblastsOsteoclastsOsteogenesisOsteoporosisOutcomePathogenicityPathologyPatientsPharmacologyPhosphorusPolyamine CatabolismPolyaminesPorosityProductionProteinsPutrescineRegimenRenal functionReportingResearchResearch PersonnelResearch Project GrantsRodentRoleSerumSnyder-Robinson syndromeSpermidineSpermineSpermine SynthaseSupplementationTestingTherapeuticTransferaseTransgenic OrganismsUp-RegulationVascular calcificationWorkbasebonebone fragilitybone lossbone turnovercalcium phosphatecell growthcomorbidityfracture riskimprovedin vivoinnovationiron deficiencyloss of function mutationmineralizationmortalitynew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsosteoblast differentiationpolyamine oxidasepreservationprotective effectsmall moleculestem cellstranslational 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:
骨脆性增加骨折风险是矿物质和骨病的定义成分之一
慢性肾脏病(CKD-MBD)。慢性肾脏病患者的骨内环境平衡失调与
持续骨折的CKD患者的发病率和死亡率较高。另外,
无法维持正常的骨内环境平衡会导致循环钙磷升高和
血管钙化的发展。腺嘌呤饮食诱导的小鼠肾功能衰竭模型
与CKD患者骨活检平行的病理性骨改变,包括孔洞和破骨细胞增多
数。这些组织学特征与缺铁性贫血的发展同时发生。
在慢性肾脏病中经常发生。然而,铁处理中断对骨骼稳态的直接影响
在肾功能衰竭期间仍不清楚。先前的研究发现,缺铁会阻碍骨形成,
在喂养缺铁饮食的啮齿类动物中,头盖骨成骨细胞。最近的研究发现,缺铁
改变细胞多胺的合成,最终减少精胺和亚精胺的含量。精胺和
有趣的是,人们已经发现亚精胺对成骨细胞的分化和功能很重要。
与对照组相比,CKD患者的精胺水平也被观察到降低。一元化
这一建议的假设是CKD-MBD及其关键部分的成骨细胞分化受到损害
缺铁导致多胺合成减少是其病理生理机制之一。我们致力于这条新奇的道路
在这项斯蒂芬·I·卡茨早期研究员研究补助金中,有两个具体目的的研究。在目标1中,
我们将验证缺铁介导的精胺减少抑制成骨细胞的假设。
差异化。这将通过评估在缺铁期间补充精胺来实现。
在体外和体内的条件。先前的研究表明,缺铁可能会使精胺变钝。
通过还原精胺合成酶进行转化。因此,我们还将对骨保护性转基因进行检测
慢性肾脏病缺铁时精胺合成酶表达上调。最后,要确定这些小的
分子改变基因表达,我们将进行表观遗传测序研究,因为缺铁和
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促进多胺分解代谢的假说。在……里面
患者研究发现,与对照组相比,CKD血清精胺氧化酶活性升高。
此外,缺铁会增加分解精胺的N-乙酰转移酶蛋白水平。我们会
对慢性肾脏病缺铁期间进行遗传和药物抑制以解决这些新的问题
问题。这些研究的完成将大大提高我们对骨稳态的了解。
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。
用于缺铁和CKD-MBD。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Erica L Clinkenbeard其他文献
Zhx2 and the balance between cardiovascular and hepatic health
Zhx2与心血管和肝脏健康之间的平衡
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
K. Creasy;Erica L Clinkenbeard;B. Spear - 通讯作者:
B. Spear
The metabolic bone disease associated with the Hyp mutation is independent of osteoblastic HIF1α expression
与 Hyp 突变相关的代谢性骨病与成骨细胞 HIF1α 表达无关
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:2.5
- 作者:
J. Hum;Erica L Clinkenbeard;Colin Ip;Taryn A. Cass;M. Allen;K. White - 通讯作者:
K. White
INSIGHTS INTO HEPATIC ALPHA- FETOPROTEIN GENE REGULATION DURING LIVER DEVELOPMENT AND DISEASE
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
Erica L Clinkenbeard - 通讯作者:
Erica L Clinkenbeard
Erica L Clinkenbeard的其他文献
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{{ truncateString('Erica L Clinkenbeard', 18)}}的其他基金
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
- 批准号:
10803535 - 财政年份:2021
- 资助金额:
$ 40.21万 - 项目类别:
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
- 批准号:
10540418 - 财政年份:2021
- 资助金额:
$ 40.21万 - 项目类别:
Role of iron and hypoxia sensing in FGF23-dependent metabolic bone disease
铁和缺氧传感在 FGF23 依赖性代谢性骨病中的作用
- 批准号:
8712989 - 财政年份:2014
- 资助金额:
$ 40.21万 - 项目类别:
Role of iron and hypoxia sensing in FGF23-dependent metabolic bone disease
铁和缺氧传感在 FGF23 依赖性代谢性骨病中的作用
- 批准号:
9055645 - 财政年份:2014
- 资助金额:
$ 40.21万 - 项目类别:
Role of iron and hypoxia sensing in FGF23-dependent metabolic bone disease
铁和缺氧传感在 FGF23 依赖性代谢性骨病中的作用
- 批准号:
8850699 - 财政年份:2014
- 资助金额:
$ 40.21万 - 项目类别:
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