Parathyroid Hormone: Genetic Architecture and Clinical Consequences

甲状旁腺激素：遗传结构和临床后果

• 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
• 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

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.

项目总结 这份提案描述了一项为期3年的职业发展计划和研究战略，通过该战略， 候选人将通过基因组科学和研究能力加强她的临床流行病学专业知识 生物信息学和研究甲状旁腺激素浓度的遗传基础。 首席研究员在华盛顿大学(UW)完成了流行病学博士学位，并且 北京大学医学院肾脏内科肾脏研究所博士后培训 UW。她将通过有重点的职业发展计划和培训来扩展她的科学技能 分子遗传学在成人甲状旁腺激素失调中的应用。布鲁斯·帕萨蒂博士是 他在威斯康星州大学医学院工作，并将指导首席研究员的科学和职业发展。帕萨蒂博士是一位 全球公认的心血管疾病遗传流行病学领域的领导者。的一个咨询委员会 科学家，包括Deborah Nickerson博士，他在应用稳健的方法研究Next- 世代测序技术和著名生物统计学家罗尼特·卡茨博士将提供 额外的职业和项目指导。此外，在威斯康星大学和寒冬大学的密集研讨会、课程作业 斯普林港实验室，德克萨斯大学健康学院的一个奖学金项目，研讨会，期刊俱乐部，和特定分析 技术培训将伴随着充足的保护性研究时间。大学里的学术环境 威斯康星大学肾脏病学系支持发展独立的转化型研究人员。 科学研究将集中在循环甲状旁腺激素(PTH)的遗传机制上 甲状旁腺激素紊乱具有重要的临床意义 后果。原发性甲状旁腺功能亢进症通常与骨病、肾结石和 胃肠动力障碍。继发性甲状旁腺功能亢进在慢性肾脏疾病中的进行性发展 (CKD)，在CKD的发病机制中起作用--矿物质和骨骼紊乱。在普通人群中，更高 血清甲状旁腺素浓度与高血压、左心室肥厚和骨折有关。 钙稳态所必需的调节激素。 这个 甲状旁腺激素的潜在调节机制尚不清楚，存在显著的相互作用。 甲状旁腺素的个体差异不受已知因素的影响。甲状旁腺激素的全基因组关联研究 浓度显示，与CYP24A1基因附近的一个常见变异有很强的相关性。 CYP24A1编码活性维生素D的主要分解代谢酶，在钙离子中起关键作用 新陈代谢，突出表现为发现失活突变是导致高钙血症的原因之一 肾结石。这些数据首次证明维生素D分解代谢与甲状旁腺素调节有关。 该项目的具体目标是通过以下方式扩展这些发现：1)识别与 循环甲状旁腺素，2)精确定位与甲状旁腺素浓度相关的功能变异，以及3)估计 血清甲状旁腺素浓度与高血压、心力衰竭和骨折的明确因果关系 使用孟德尔随机化方法。