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
• 负责人: Marciana Lee Laster
• 金额: $ 20.2万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/10380577
• 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 group; Etiology; Exposure to; Foundations; Fracture; Gene Proteins; Genes; Genetic; Genetic Research; Genetic Variation; Goals; Gold; 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; Pediatric Research; Phenotype; Physiology; Population; Prevalence; Quality of life; Race; Receptor Gene; Renal Osteodystrophy; Research Design; Research Personnel; Risk; Role; Scientist; Secondary Hyperparathyroidism; Serum; Single Nucleotide Polymorphism; Skeletal system; Sterols; Suggestion; Therapeutic; Therapeutic Intervention; Time; Training; Universities; Variant; Vascular calcification; Vitamin D; Vitamin D-Binding Protein; Vitamin D3 Receptor; Work; base; bone; bone turnover; cardiovascular health; cohort; comorbidity; diagnosis standard; epidemiologic data; ethnic difference; genetic association; genetic epidemiology; genetic predictors; genetic variant; genome wide association study; hormone resistance; improved; individualized medicine; mortality; novel; patient population; pediatric patients; premature; racial and ethnic; racial difference; response; skeletal; skeletal abnormality; skills; translational scientist; treatment guidelines; young adult

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 这是加利福尼亚大学Los的Marciana Lanster博士的K23申请的最初提交 安吉利斯（加州大学洛杉矶分校）。候选人：该提案中Laster博士的培训对象包括：1）发展专业知识 PTH-VITAMIN D轴的生理和遗传学，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方法以及3） 在评估骨骼组织计量学评估骨转换方面的专业知识。 Laster博士将完成 这些活动通过思想，课程和参加研讨会的活动。她聚集了一个团队 科学家包括她的主要导师Isidro Salusky博士，儿科CKD-MBD和Co-Mentor Dr. 维生素D代谢专家Ravi Thadhani。研究：小儿CKD-MBD几乎影响所有儿科 CKD患者到达透析时。尽管有多年的活性维生素D固醇治疗，但 骨骼发病率和心血管死亡率仍然不可接受。 Laster博士的长期目标是 个性化儿科CKD-MBD的治疗，以改善儿科的健康和生活质量 CKD患者。实现这一目标的第一步涉及鉴定遗传变异 预测PTH水平和对PTH水平的骨骼反应。 Laster博士假设次要的风险 甲状旁腺功能亢进症和CKD中的PTH反应性程度通过遗传差异预测 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Laster博士的 她展示了临床结果的初步工作 非裔美国人。该PTH抗性的遗传基础得到了证明选择遗传的研究 在非裔美国人中经常发现的变体，这些变体与临床图片有关 PTH抗性。在AIM 1中，Laster博士将在VDR和VDBP基因中识别SNP，以解释变化 在PTH水平上使用1076例患者的DIALYSIS CKD队列和100例透析队列。这个目标 将确定VDR和VDBP中的SNP与小儿CKD中的血清PTH水平相关联 人口。在AIM 2中，Laster博士将识别VDR和VDBP中的SNP，以解释PTH调整后的变化 骨转换。这个目标将建立与骨头对高程的可变响应相关的SNP 在PTH（即PTH抗性）中。在AIM 3中，Laster博士将在1076年进行基因组广泛的关联研究 小儿透析前CKD患者为了识别解释PTH水平差异的新型SNP。博士 懒惰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 小儿CKD-MBD疗法的强度。