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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：
Marciana Lee Laster
金额：
$ 20.16万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
https://reporter.nih.gov/project-details/10592364
关键词：
Adult Affect African American African American population Behavior Biochemical Biometry Bone Diseases California Cardiac Cardiovascular system Caucasians Child Childhood Chronic Kidney Failure Clinical Complex Coupled Data Deformity Dialysis patients Dialysis procedure Educational workshop End stage renal failure Ethnic Origin Ethnic Population Etiology Exposure to Foundations Fracture Gene Proteins Genes Genetic Genetic Research Genetic Variation Goals Growth Guidelines Health Hormone Responsive Hypercalcemia Knowledge Learning Life Style Los Angeles Measures Mediating Medical Genetics Mentors Mentorship Metabolism Minerals Morbidity - disease rate Osteoclasts Osteogenesis Outcome PTH gene Patients Phenotype Physiology Population Prevalence Quality of life Race Receptor Gene Recommendation Renal Osteodystrophy Research Research Design Research Personnel Risk Role Scientist Secondary Hyperparathyroidism Serum Single Nucleotide Polymorphism Skeletal system Sterols Therapeutic Therapeutic Intervention Time Training Universities Variant Vascular calcification Vitamin D Vitamin D-Binding Protein Vitamin D3 Receptor Work bone bone turnover cardiovascular health cohort comorbidity diagnosis standard epidemiologic data ethnic difference genetic association genetic epidemiology genetic predictors genetic selection genetic variant genome wide association study hormone resistance improved individualized medicine mortality novel patient population pediatric patients premature racial difference racial population response skeletal skeletal abnormality skills translational scientist treatment guidelines young 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。