Vitamin D Genetics and Racial Differences in Pediatric Chronic Kidney Disease-Mineral and Bone Disorder
儿科慢性肾脏病 - 矿物质和骨骼疾病的维生素 D 遗传学和种族差异
基本信息
- 批准号:10592364
- 负责人:
- 金额:$ 20.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectAfrican AmericanAfrican American populationBehaviorBiochemicalBiometryBone DiseasesCaliforniaCardiacCardiovascular systemCaucasiansChildChildhoodChronic Kidney FailureClinicalComplexCoupledDataDeformityDialysis patientsDialysis procedureEducational workshopEnd stage renal failureEthnic OriginEthnic PopulationEtiologyExposure toFoundationsFractureGene ProteinsGenesGeneticGenetic ResearchGenetic VariationGoalsGrowthGuidelinesHealthHormone ResponsiveHypercalcemiaKnowledgeLearningLife StyleLos AngelesMeasuresMediatingMedical GeneticsMentorsMentorshipMetabolismMineralsMorbidity - disease rateOsteoclastsOsteogenesisOutcomePTH genePatientsPhenotypePhysiologyPopulationPrevalenceQuality of lifeRaceReceptor GeneRecommendationRenal OsteodystrophyResearchResearch DesignResearch PersonnelRiskRoleScientistSecondary HyperparathyroidismSerumSingle Nucleotide PolymorphismSkeletal systemSterolsTherapeuticTherapeutic InterventionTimeTrainingUniversitiesVariantVascular calcificationVitamin DVitamin D-Binding ProteinVitamin D3 ReceptorWorkbonebone turnovercardiovascular healthcohortcomorbiditydiagnosis standardepidemiologic dataethnic differencegenetic associationgenetic epidemiologygenetic predictorsgenetic selectiongenetic variantgenome wide association studyhormone resistanceimprovedindividualized medicinemortalitynovelpatient populationpediatric patientsprematureracial differenceracial populationresponseskeletalskeletal abnormalityskillstranslational scientisttreatment guidelinesyoung adult
项目摘要
PROJECT SUMMARY
This is an initial submission of a K23 application by Dr. Marciana Laster from the University of California, Los
Angeles (UCLA). Candidate: Dr. Laster’s training objectives in this proposal include to: 1) develop expertise in
the physiology and genetics of the PTH-Vitamin D axis, 2) gain further skills in the management of
epidemiologic data, principles of genetic association studies and advanced bio-statistical approaches and 3)
develop expertise in the assessment of bone turnover by bone histomorphometry. Dr. Laster will accomplish
these activities through mentorship, coursework and participation in workshops. She has assembled a team of
scientists including her primary mentor Dr. Isidro Salusky, an expert in pediatric CKD-MBD and co-mentor Dr.
Ravi Thadhani, an expert in Vitamin D metabolism. Research: Pediatric CKD-MBD affects nearly all pediatric
patients with CKD by the time they reach dialysis. Despite years of treatment with active Vitamin D sterols,
skeletal morbidity and cardiovascular mortality remain unacceptably high. Dr. Laster’s long-term goal is to
individualize the treatment of pediatric CKD-MBD in order to improve the health and quality of life of pediatric
CKD patients. The first step toward accomplishing this goal involves the identification of genetic variants that
predict PTH levels and skeletal response to PTH levels. Dr. Laster hypothesizes that the risk of secondary
hyperparathyroidism and the degree of PTH responsiveness in CKD are predicted by genetic variation in the
Vitamin D Receptor (VDR) gene, which mediates PTH release and osteoclast activity, and the Vitamin D
Binding Protein (VDBP) gene, which mediates vitamin D transport and osteoclast activity. In Dr. Laster’s
preliminary work she demonstrated clinical outcomes suggestive of underlying PTH resistance amongst
African-Americans. A genetic basis of this PTH resistance is supported by studies demonstrating select genetic
variants found frequently amongst African-Americans which are associated with a clinical picture suggestive of
PTH resistance. In Aim 1, Dr. Laster will identify SNPs within the VDR and VDBP genes that explain variation
in PTH levels using a pre-dialysis CKD cohort of 1076 patients and a dialysis cohort of 100 patients. This aim
will establish how SNPs in the VDR and VDBP associate with serum PTH levels in the pediatric CKD
population. In Aim 2, Dr. Laster will identify SNPs in the VDR and VDBP that explain variation in PTH-adjusted
bone turnover. This aim will establish SNPs that are associated with a variable response of bone to elevations
in PTH (i.e. PTH resistance). In Aim 3, Dr. Laster will perform a genome wide association study in the 1076
pediatric pre-dialysis CKD patients in order to identify novel SNPs that explain variation in PTH levels. Dr.
Laster’s aims will help to establish a phenotype of skeletal response that can then be used to individualize the
intensity of pediatric CKD-MBD therapy.
项目总结
这是加州大学洛杉矶分校的Marciana Laster博士首次提交的K23申请
洛杉矶(加州大学洛杉矶分校)。候选人:雷斯特博士在这份提案中的培训目标包括:1)发展专业知识
甲状旁腺素-维生素D轴的生理学和遗传学,2)在管理方面获得进一步的技能
流行病学数据、遗传关联研究原理和先进的生物统计学方法和3)
发展通过骨组织形态计量学评估骨转换的专业知识。拉斯特博士将完成
通过辅导、课程作业和参加讲习班,开展这些活动。她已经组建了一支由
科学家包括她的主要导师伊西德罗·萨卢斯基博士、儿科CKD-MBD专家和共同导师Dr。
维他命D新陈代谢专家拉维·塔哈尼说。研究:儿科CKD-MBD影响几乎所有儿科
慢性肾脏病患者在达到透析时。尽管多年来一直使用活性维生素D类固醇进行治疗,
骨骼发病率和心血管死亡率仍然高得令人无法接受。拉斯特博士的长期目标是
对儿童CKD-MBD进行个体化治疗,提高儿童健康和生活质量
CKD患者。实现这一目标的第一步涉及识别
预测甲状旁腺素水平和骨骼对甲状旁腺素水平的反应。拉斯特博士假设,继发性心脏病的风险
CKD患者甲状旁腺功能亢进症和甲状旁腺激素反应性程度的预测
介导甲状旁腺素释放和破骨细胞活性的维生素D受体(VDR)基因和维生素D
结合蛋白(VDBP)基因,介导维生素D转运和破骨细胞活性。在拉斯特博士的
她的初步工作证明了甲状旁腺素抵抗的临床结果。
非裔美国人。这种甲状旁腺素抗性的遗传基础得到了研究的支持,这些研究证明了选择基因
在非裔美国人中经常发现的变异与临床表现相关联
耐PTH。在目标1中,拉斯特博士将确定VDR和VDBP基因中解释变异的SNPs
在甲状旁腺素水平方面,使用透析前CKD队列中的1076名患者和透析队列中的100名患者。这一目标
将确定VDR和VDBP中的SNPs如何与儿童CKD患者的血清PTH水平相关
人口。在目标2中,拉斯特博士将确定VDR和VDBP中的SNPs,这些SNPs可以解释甲状旁腺素调节后的变化
骨骼周转率。这一目标将建立与骨骼对海拔高度的可变反应相关的SNPs
在PTH中(即PTH抗性)。在目标3中,拉斯特博士将在1076进行全基因组关联研究
儿童透析前CKD患者,以确定解释甲状旁腺激素水平变化的新SNPs。Dr。
Laster的目标将有助于建立骨骼反应的表型,然后可以用来个性化
儿科CKD-MBD治疗的强度。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Progress made toward equitable transplantation in children and young adults with kidney disease.
患有肾病的儿童和年轻人在公平移植方面取得了进展。
- DOI:10.1007/s00467-024-06309-5
- 发表时间:2024
- 期刊:
- 影响因子:0
- 作者:Harford,Mercedes;Laster,Marciana
- 通讯作者:Laster,Marciana
Seeking justice, equity, diversity and inclusion in pediatric nephrology.
寻求儿科肾脏中的正义,公平,多样性和包容性。
- DOI:10.3389/fped.2022.1084848
- 发表时间:2022
- 期刊:
- 影响因子:2.6
- 作者:
- 通讯作者:
Equitable Transplantation: A Modifiable Risk Factor for Disparities in Mortality in ESKD.
公平移植:ESKD 死亡率差异的可改变风险因素。
- DOI:10.1681/asn.2022030273
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Laster,Marciana;Norris,KeithC
- 通讯作者:Norris,KeithC
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Marciana Lee Laster其他文献
Marciana Lee Laster的其他文献
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{{ truncateString('Marciana Lee Laster', 18)}}的其他基金
Vitamin D Genetics and Racial Differences in Pediatric Chronic Kidney Disease-Mineral and Bone Disorder
儿科慢性肾脏病 - 矿物质和骨骼疾病的维生素 D 遗传学和种族差异
- 批准号:
10380577 - 财政年份:2020
- 资助金额:
$ 20.16万 - 项目类别:
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