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.
项目总结/文摘:
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:
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:
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:
8850699 - 财政年份:2014
- 资助金额:
$ 40.21万 - 项目类别:
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