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:
- 金额:$ 39.13万
- 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:AcetyltransferaseAddressAdenineAffectAmericanAutomobile DrivingAwardBiopsyBone DiseasesBone Formation InhibitionBone MarrowBone ResorptionCalciumCalvariaCatabolismCell Differentiation processCellsChronicChronic Kidney FailureCouplingDNADevelopmentDietDiseaseEnzymesEpigenetic ProcessExhibitsFoundationsFractureFunctional disorderGene ExpressionGeneral PopulationGeneticHip FracturesHistologicHomeostasisImpairmentIn VitroInterventionIronIron deficiency anemiaKidney FailureKnowledgeLinkMediatingMetabolismMineralsMissionModelingMorbidity - disease rateMorphologyMusOsteoblastsOsteoclastsOsteogenesisOsteoporosisOutcomePathogenicityPathologyPatientsPhosphorusPolyamine CatabolismPolyaminesPorosityProductionProteinsPutrescineRegimenRenal functionReportingResearchResearch PersonnelResearch Project GrantsRodentRoleSerumSnyder-Robinson syndromeSpermidineSpermineSpermine SynthaseSupplementationTestingTherapeuticTransferaseTransgenic OrganismsUp-RegulationVascular calcificationWorkbonebone fragilitybone lossbone turnovercell growthcomorbiditycomparison controlfracture riskimprovedin vivoinnovationinorganic phosphateiron deficiencyloss of function mutationmineralizationmortalitynew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsosteoblast differentiationoverexpressionpharmacologicpolyamine 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
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:
10333851 - 财政年份:2021
- 资助金额:
$ 39.13万 - 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:
$ 39.13万 - 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:
$ 39.13万 - 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:
$ 39.13万 - 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:
$ 39.13万 - 项目类别:
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