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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.

项目摘要这是来自洛杉矶加州大学的马尔恰纳·拉斯特博士首次提交的K23申请洛杉矶（UCLA）.候选人：拉斯特博士在本建议书中的培训目标包括：1）发展以下方面的专业知识 PTH-维生素D轴的生理学和遗传学，2）获得管理的进一步技能，流行病学数据、遗传关联研究原理和先进的生物统计方法，以及3）发展通过骨组织形态计量学评估骨转换的专业知识。拉斯特博士会完成这些活动通过指导、课程和参加讲习班进行。她召集了一个包括她的主要导师Isidro Salusky博士，儿童CKD-MBD专家和共同导师Dr. Ravi Thadhani，维生素D代谢专家。研究：小儿CKD-MBD影响几乎所有儿童 CKD患者达到透析时。尽管用活性维生素D固醇治疗多年，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个性化治疗儿童CKD-MBD，以改善儿童的健康和生活质量 CKD患者。实现这一目标的第一步涉及识别遗传变异，预测PTH水平和骨骼对PTH水平的反应。拉斯特博士假设， CKD患者的甲状旁腺功能亢进和PTH反应性程度可通过维生素D受体（VDR）基因，介导PTH释放和破骨细胞活性，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。在拉斯特医生的她的初步工作表明，临床结果提示潜在的PTH抵抗，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，这些研究表明选择性遗传在非裔美国人中经常发现的变异，这些变异与提示以下疾病的临床表现有关： PTH电阻。在目标1中，Laster博士将确定VDR和VDBP基因中解释变异的SNP 使用1076例CKD患者的透析前队列和100例患者的透析队列，这一目标将确定VDR和VDBP中的SNP如何与儿童CKD中的血清PTH水平相关人口在目标2中，Laster博士将确定VDR和VDBP中的SNP，这些SNP可以解释PTH调整的骨转换这一目标将建立与骨骼对海拔变化的反应相关的SNP 在PTH中（即PTH电阻）。在目标3中，拉斯特博士将在1076年进行全基因组关联研究。儿童透析前CKD患者，以确定解释PTH水平变化的新SNP。博士拉斯特的目标将有助于建立骨骼反应的表型，然后可用于个性化治疗。儿童CKD-MBD治疗强度。