Parathyroid Hormone: Genetic Architecture and Clinical Consequences

甲状旁腺激素：遗传结构和临床后果

基本信息

批准号：
9495068
负责人：
Cassianne Robinson-Cohen
金额：
$ 13.78万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-19 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9495068
关键词：
Adult Advisory Committees Alleles Architecture Bioinformatics Biological Biology Bone Density Bone Diseases CLDN14 gene Calcium Cardiovascular Diseases Catabolism Chronic Kidney Failure Clinical Complex Data Data Set Databases Development Development Plans Dihydroxycholecalciferols Disease Disease of parathyroid glands Doctor of Philosophy Educational workshop Elements Environment Enzymes Epidemiology Epigenetic Process Fellowship Program Fracture Gene Expression General Population Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Screening Genetic Variation Genome Genomics Goals Health Heart failure Homeostasis Hormone use Hormones Hypercalcemia Hyperparathyroidism Hypertension Individual Investigation Journals Kidney Kidney Calculi Laboratories Lead Left Ventricular Hypertrophy Link Medicine Mendelian disorder Mentors Metabolic Diseases Methods Minerals Minor Molecular Genetics Mutation Nephrolithiasis Nephrology Outcome PTH gene Pathogenesis Patients Play Positioning Attribute Principal Investigator Program Development Proteins Randomized Research Research Institute Risk Role Science Scientist Secondary Hyperparathyroidism Serum Signal Transduction Technology Tight Junctions Time Training Training Technics Twin Studies Universities Variant Vitamin D Washington adverse outcome bone calcium metabolism career career development clinical epidemiology design exome gastrointestinal genetic analysis genetic association genetic epidemiology genetic variant genome wide association study genome-wide hormone regulation improved inorganic phosphate inter-individual variation motility disorder next generation sequencing novel novel therapeutics phosphorus metabolism post-doctoral training precision medicine professor rare variant renal calcium skills translational scientist

项目摘要

PROJECT SUMMARY This proposal describes a 3-year career development program and research strategy through which the Candidate will bolster her clinical epidemiology expertise with research capacity in genome science and bioinformatics and investigate the genetic underpinnings of parathyroid hormone concentrations. The principal investigator has completed a PhD at the University of Washington (UW) in Epidemiology, and post-doctoral training at the Kidney Research Institute, Division of Nephrology, Department of Medicine at the UW. She will expand upon her scientific skills through a focused career development plan and training in molecular genetics as applied to parathyroid hormone dysregulation in adults. Dr. Bruce Psaty is Professor of Medicine at UW and will mentor the principal investigator's scientific and career development. Dr. Psaty is a globally recognized leader in the genetic epidemiology of cardiovascular disease. An advisory committee of scientists, including Dr. Deborah Nickerson who has expertise in the applying robust methods for next- generation sequencing technology and Dr. Ronit Katz who is a well-established biostatistician, will provide additional career and project guidance. In addition, intensive workshops, coursework at UW and the Cold Spring Harbor Laboratory, a fellowship program at UT Health, seminars, journal clubs, and specific analytic technique training will accompany ample protected research time. The academic environment in the Department of Nephrology at UW supports the development of independent, translational investigators. Scientific investigations will focus on the genetic mechanisms of circulating parathyroid hormone (PTH), the Disorders of PTH have important clinical consequences. Primary hyperparathyroidism is classically associated with bone disease, kidney stones, and gastrointestinal dysmotility. Secondary hyperparathyroidism develops progressively in chronic kidney disease (CKD), contributing to the pathogenesis of CKD-mineral and bone disorder. In the general population, higher serum PTH concentrations are associated with hypertension, left ventricular hypertrophy, and fractures. essential regulatory hormone for calcium homeostasis. The underlying regulatory mechanism for of parathyroid hormone is unknown and there exists marked inter- individual variation in PTH independent of known factors. A recent genome-wide association study of PTH concentrations revealed a robust and strong association for a common variant near the CYP24A1 gene. CYP24A1 encodes the primary catabolic enzyme for active vitamin D and plays a critical role in calcium metabolism, highlighted by the discovery of inactivating mutations as a cause of hypercalcemia and nephrolithiasis. These data represent the first evidence that vitamin D catabolism is related to PTH regulation. The specific goals of this project are to extend these findings, by: 1) identifying rare variants associated with circulating PTH, 2) pinpointing functional variants associated with PTH concentrations, and 3) estimating the unconfounded causal association of serum PTH concentrations with hypertension, heart failure, and fracture using a Mendelian randomization approach.

项目摘要该建议描述了一个为期3年的职业发展计划和研究策略候选人将通过基因组科学研究能力和生物信息学并研究甲状旁腺激素浓度的遗传基础。首席研究员已在华盛顿大学（UW）的流行病学完成博士学位，并完成医学系肾脏研究所肾脏研究所的博士后培训 UW。她将通过重点的职业发展计划和培训来扩展自己的科学技能分子遗传学应用于成年人的甲状旁腺激素失调。 Bruce Psaty博士是西澳大学的医学，将指导主要研究者的科学和职业发展。 Psaty博士是心血管疾病遗传流行病学的全球公认领导者。一个咨询委员会科学家，包括黛博拉·尼克森（Deborah Nickerson 生成测序技术和一位成熟的生物统计学家的Ronit Katz博士将提供其他职业和项目指导。此外，密集的研讨会，UW的课程和寒冷 Spring Harbour Laboratory，UT Health的奖学金计划，研讨会，期刊俱乐部和特定的分析技术培训将伴随大量受保护的研究时间。学术环境 UW的肾脏病科支持独立，转化调查人员的发展。科学研究将重点介绍循环甲状旁腺激素（PTH）的遗传机制， PTH的疾病具有重要的临床结果。原发性甲状旁腺功能亢进与骨骼疾病，肾结石和胃肠道不一致。继发性甲状旁腺功能亢进在慢性肾脏疾病中逐渐发展（CKD），导致CKD时代疾病和骨骼疾病的发病机理。在一般人群中，较高血清PTH浓度与高血压，左心室肥大和骨折有关。钙稳态的基本调节激素。这甲状旁腺激素的基本调节机制尚不清楚，并且存在于 PTH的个体变异与已知因素无关。 PTH的最新全基因组关联研究浓度揭示了CYP24A1基因附近的常见变体有牢固而强的关联。 CYP24A1编码主活性维生素D的主要分解代谢酶，并在钙中起关键作用代谢，发现失活突变是高钙血症和肾结石病。这些数据代表了维生素D分解代谢与PTH调节有关的第一个证据。该项目的具体目标是扩展这些发现，通过：1）确定与之相关的稀有变体循环PTH，2）指出与PTH浓度相关的功能变体，3）估计血清PTH浓度与高血压，心力衰竭和骨折的无关因果关系使用孟德尔随机方法。