Targeting sKlotho-FGF23 Interactions to Improve Pathological Phosphate Handling in CKD
Targeting sKlotho-FGF23 Interactions to Improve Pathological Phosphate Handling in CKD
批准号:
10553159
负责人:
KENNETH E WHITE
金额:
$44.25万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-03-15 至 2025-01-31
关键词:
AccelerationAcuteAffectAllelesBinding ProteinsBiochemicalBiological ProcessBiologyBreedingCRISPR/Cas technologyCell surfaceCellsCellular MembraneChronicChronic Kidney FailureClinicalComplexDataData SetDefectDiseaseDissectionEtiologyEventExhibitsExperimental GeneticsFGFR1 geneFamilial hypophosphatemic bone diseaseFamilial tumoral calcinosisFibroblast Growth Factor ReceptorsFractureFunctional disorderGenesGeneticGenetic CrossesGenetic ModelsHomeostasisHormonesHumanHypophosphatemiaImpairmentIn VitroIndividualInjectionsKidneyKidney DiseasesKnockout MiceLeadLongevityLoxP-flanked alleleMAP Kinase GeneMediatingMembraneMetabolismMineralsModelingMolecularMusMutationNephronsOnset of illnessOrganOsteomalaciaPathogenesisPathologicPathway interactionsPatientsPeptide HydrolasesPhenotypePhysiologicalPlasmaPlayPreventionProductionProtein IsoformsProximal Kidney TubulesRegulationRenal MassReportingResistanceResolutionRicketsRoleSecondary toSerumSeveritiesSignal TransductionSiteStructureSyndromeTechniquesTestingTimeTissuesValidationVascular calcificationautosomebeta-site APP cleaving enzyme 1cell typedesigndietaryextracellularfibroblast growth factor 23functional lossimprovedin vivoin vivo Modelinorganic phosphateinsightloss of function mutationmortalitynew therapeutic targetnovelnovel therapeuticsnuclear factors of activated T-cellspositional cloningpreventrare mendelian disorderreceptorresponsesequencing platformsingle-cell RNA sequencingtissue injurywasting
中文摘要
项目摘要/摘要:研究受干扰矿物质引起的疾病的分子病因学
代谢在鉴定磷酸盐体内平衡的新循环调节剂中起作用。我们
通过定位克隆方法分离基因,鉴定成纤维细胞生长因子-23(FGF23
常染色体显性遗传性低磷酸盐血症性佝偻病(ADHR),特征为
继发于肾性磷酸盐消耗、佝偻病/骨软化和骨折的低磷酸盐血症。FGF23
辅助受体α-Klotho(KL)与典型FGF受体(FGFR)以异聚复合物形式起作用,
正常的磷酸盐代谢所需。这是强调的事实,KL功能丧失
突变导致终末器官FGF 23抗性,并导致ADHR表型相互失调,
家族性肿瘤性钙质沉着症(hfTC)。类似地,慢性肾病患者
慢性肾脏病(CKD)患者由于功能性肾脏质量的丧失而表现出受损的FGF 23-反应性,
Klotho表达减少,导致血清磷酸盐浓度增加,
FGF23生产。KL表达为膜结合蛋白("mKL"),其介导FGF23依赖性
在靶组织中的信号传导,以及来源于蛋白水解的主要循环种类,
mKL在其近胞外膜结构域内裂解以衍生可溶形式或"sKL"。虽然
最近对FGF 23-sKL-FGFR 1三重晶体结构的解析揭示了对静态sKL-FGF 23的深入了解,
通过相互作用,mKL相对于sKL在控制FGF 23和矿物质代谢中的生物学功能的完整范围被确定。
由于缺乏适当的体内模型,代谢仍然不清楚。我们在小鼠中的初步研究
sKL基因表达的降低显示了FGF23的异常产生,
挑战与全球KL-KO小鼠不同,该模型具有寿命延长的优点,
研究,提供了新的机会,以获得关键的洞察力,调节FGF23的生物活性,在慢性
条件总的来说,我们的研究结果支持了确定特定sKL-FGF23相互作用的机制目标,
磷酸盐代谢的控制,以及测试sKL作为治疗
人类疾病本提案中要检验的中心假设是:需要Klotho的sKL形式
用于正常的FGF23介导的磷酸盐处理,并在肾脏疾病期间具有保护作用。我们期望我们
研究采用了尖端的体内和体外技术,以提供新的、转化的见解
磷酸盐代谢的基础生物学,以及改变的罕见和常见综合征,
Klotho和FGF23表达。
英文摘要
Project Summary/Abstract: Investigating the molecular etiology of disorders caused by disturbed mineral
metabolism has been instrumental in identifying new circulating regulators of phosphate homeostasis. We
identified Fibroblast growth factor-23 (FGF23) in a positional cloning approach to isolate the gene
responsible for autosomal dominant hypophosphatemic rickets (ADHR), characterized by
hypophosphatemia secondary to renal phosphate wasting, rickets/osteomalacia, and fracture. The FGF23
co-receptor alpha-Klotho (KL), acting in a heteromeric complex with a canonical FGF receptor (FGFR), is
required for normal phosphate metabolism. This is emphasized by the fact that KL loss of function
mutations lead to end-organ FGF23 resistance, and cause the phenotypic reciprocal disorder to ADHR,
hyperphosphatemic familial tumoral calcinosis (hfTC). In a similar manner, patients with chronic kidney
disease (CKD) demonstrate impaired FGF23-responsiveness due to a loss of functional kidney mass and
reduced Klotho expression, leading to increased serum phosphate concentrations and further increases in
FGF23 production. KL is expressed as a membrane-bound protein (`mKL') that mediates FGF23-dependent
signaling in target tissues, as well as a major circulating species that originates from the proteolytic
cleavage of mKL within its juxta-extracellular membrane domain to derive a soluble form or `sKL'. Although
the recent solving of the FGF23-sKL-FGFR1 triple crystal structure revealed insight into static sKL-FGF23
interactions, the complete scope of mKL versus sKL biological functions in the control of FGF23 and mineral
metabolism remains unclear due to a lack of appropriate in vivo models. Our initial studies in mice with
genetically reduced sKL expression showed aberrant FGF23 production in response to dietary phosphate
challenges. Unlike global KL-KO mice, this model has the advantage of a lifespan that allows extended
studies, providing new opportunities to gain critical insight into the regulation of FGF23 bioactivity in chronic
conditions. Collectively, our results support mechanistic aims to identify specific sKL-FGF23 interactions in
the control of phosphate metabolism, as well as to test sKL as a translational target in the treatment of
human disorders. The central hypothesis to be tested in this proposal is: the sKL form of Klotho is required
for normal FGF23-mediated phosphate handling and is protective during renal disease. We expect our
studies using dovetailed, cutting-edge in vivo and in vitro techniques to provide novel, translational insight
into the basic biology of phosphate metabolism, as well as into both rare and common syndromes of altered
Klotho and FGF23 expression.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Novel Therapy for Hyperphosphatemic Familial Tumoral Calcinosis (hfTC) and Generalized Hyperphosphatemia
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批准号:10818072
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项目类别:
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资助金额:$30.19万
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财政年份:2023
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负责人:KENNETH E WHITE
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依托单位:
Targeting sKlotho-FGF23 Interactions to Improve Pathological Phosphate Handling in CKD
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批准号:10363719
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项目类别:
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资助金额:$44.25万
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财政年份:2021
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负责人:KENNETH E WHITE
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依托单位:
Targeting sKlotho-FGF23 Interactions to Improve Pathological Phosphate Handling in CKD
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批准号:10183835
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资助金额:$45.71万
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FGF23 induction in phosphate-responsive single cells
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Novel Control of FGF23 in Metabolic Bone Disease
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批准号:9751286
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项目类别:
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资助金额:$23.26万
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财政年份:2018
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负责人:KENNETH E WHITE
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依托单位:
Control of FGF23 Bioactivity via Circulating alpha-Klotho
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批准号:8811420
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项目类别:
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资助金额:$33.93万
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财政年份:2013
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负责人:KENNETH E WHITE
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依托单位:
Control of FGF23 Bioactivity via Circulating alpha-Klotho
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批准号:9012815
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项目类别:
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资助金额:$33.93万
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财政年份:2013
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负责人:KENNETH E WHITE
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依托单位:
Control of FGF23 Bioactivity via Circulating alpha-Klotho
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批准号:8636471
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项目类别:
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资助金额:$33.93万
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财政年份:2013
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负责人:KENNETH E WHITE
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依托单位:
Control of FGF23 Bioactivity via Circulating alpha-Klotho
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批准号:8503007
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项目类别:
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资助金额:$33.93万
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财政年份:2013
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负责人:KENNETH E WHITE
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依托单位:
Conditional Isolation of Fgf23 Activity
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批准号:8152113
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项目类别:
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资助金额:$19.96万
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财政年份:2010
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负责人:KENNETH E WHITE
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依托单位:
Conditional Isolation of Fgf23 Activity
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批准号:8046214
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项目类别:
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资助金额:$17.33万
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财政年份:2010
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负责人:KENNETH E WHITE
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依托单位:
FGF-23 REGULATION OF PHOSPHATE HOMEOSTASIS
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批准号:7990118
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项目类别:
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资助金额:$5.0万
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财政年份:2009
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负责人:KENNETH E WHITE
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依托单位:
FGF-23 REGULATION OF PHOSPHATE HOMEOSTASIS
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批准号:6986698
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项目类别:
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资助金额:$22.63万
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财政年份:2002
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负责人:KENNETH E WHITE
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依托单位:
FGF-23 REGULATION OF PHOSPHATE HOMEOSTASIS
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批准号:6826844
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项目类别:
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资助金额:$23.18万
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财政年份:2002
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负责人:KENNETH E WHITE
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依托单位:
FGF-23 REGULATION OF PHOSPHATE HOMEOSTASIS
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批准号:7558270
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项目类别:
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资助金额:$32.09万
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财政年份:2002
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负责人:KENNETH E WHITE
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依托单位:
FGF-23 REGULATION OF PHOSPHATE HOMEOSTASIS
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批准号:6556963
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项目类别:
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资助金额:$23.18万
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财政年份:2002
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负责人:KENNETH E WHITE
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依托单位:
FGF-23 REGULATION OF PHOSPHATE HOMEOSTASIS
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批准号:7372256
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项目类别:
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资助金额:$32.15万
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财政年份:2002
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负责人:KENNETH E WHITE
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依托单位:
FGF-23 Regulation of Phosphate Homeostasis
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批准号:8236562
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项目类别:
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资助金额:$33.86万
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财政年份:2002
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负责人:KENNETH E WHITE
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依托单位:
FGF-23 REGULATION OF PHOSPHATE HOMEOSTASIS
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批准号:6692972
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项目类别:
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资助金额:$23.18万
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财政年份:2002
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负责人:KENNETH E WHITE
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依托单位:
FGF-23 REGULATION OF PHOSPHATE HOMEOSTASIS
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批准号:7743404
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资助金额:$31.77万
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财政年份:2002
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负责人:KENNETH E WHITE
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依托单位:
海外基金