Regulation of serum vitamin D (calcidiol - 25(OH)D) by CYP2R1

CYP2R1 对血清维生素 D（骨化二醇 - 25(OH)D）的调节

• 批准号: 9087394
• 负责人: Jeffrey David Roizen
• 金额: $ 12.92万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9087394
• 关键词: 25-hydroxyvitamin D; Address; Advisory Committees; Affect; Anesthesia procedures; Award; Biochemical; Bioinformatics; Biological; Bone Density; Calcifediol; Calcium; Cellular biology; Child; Childhood; Clinical; Defect; Diabetes Mellitus; Disease; Doctor of Medicine; Doctor of Philosophy; Drug or chemical Tissue Distribution; Early identification; Early treatment; Electrophoretic Mobility Shift Assay; Endocrine; Endocrine Physiology; Endocrine System Diseases; Endocrinology; Environment; Enzymes; Extrahepatic; Fathers; Fellowship; Fertility; Foundations; Functional disorder; Generations; Genes; Genetic; Genetic Determinism; Genetic Transcription; Genetic Variation; Genomics; Genotype; Goals; Gonadal structure; Head; Heterogeneity; Homeostasis; Hydroxylation; Immunohistochemistry; In Vitro; Individual; Insulin-Dependent Diabetes Mellitus; Intake; K-Series Research Career Programs; Klinefelter' s Syndrome; Knock-in; Knockout Mice; Link; Liver; Mediating; Mentors; Mentorship; Metabolism; Mixed Function Oxygenases; Molecular Biology; Mus; National Research Service Awards; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Organ; Ovary; Pathology; Patients; Pediatric Hospitals; Pediatrics; Philadelphia; Phosphorus; Physicians; Physiologic calcification; Physiology; Play; Postdoctoral Fellow; Process; Production; RNA Interference; Regulation; Reporter; Research; Research Support; Resources; Risk; Risk Assessment; Role; SECTM1 gene; Science; Scientist; Serum; Single Nucleotide Polymorphism; Societies; Spermatogonia; Staging; Staining method; Stains; Sum; Sunlight; Supplementation; Techniques; Testing; Testis; Testosterone; Tissues; Training; Training Programs; Training and Infrastructure; Transcriptional Regulation; Translational Research; Variant; Vitamin D; Vitamin D supplementation; Work; adenoviral-mediated; aged; arm; base; bone health; career; career development; clinical practice; cohort; disorder risk; genetic profiling; genome wide association study; improved; instructor; knock-down; mid-career faculty; mortality; novel; offspring; overexpression; pediatric department; precision medicine; professor; promoter; public health relevance; response; screening; skills; transcription factor

 DESCRIPTION (provided by applicant): This proposal describes a three-year training program to develop an independent research career in endocrine physiology. The candidate is an instructor and attending in pediatric endocrinology at the Children's Hospital of Philadelphia (CHOP), with an M.D.-Ph.D. in molecular and cell biology. He extended his training engaged in intensive translational research supported by the Department of Pediatrics Ruth L. Kirschstein National Research Service Award (T32), the Pediatric Endocrine Society (PES) Research Fellowship and the Endocrine Society Clinical Scholars Award and is currently supported by the Division of Endocrinology and Diabetes Career Development Award in Pediatric Diabetes Research (K12), a career development award from the Clinical Practice Enhancement and Anesthesia Research Foundation and the PES Clinical Scholar Award. The proposed research will enhance our understanding of vitamin D metabolism and physiology. Vitamin D insufficiency is common and is thought to reflect insufficient sunlight-dependent synthesis or intake of vitamin D. Low 25-hydroxyvitamin D (calcidiol - 25(OH)D) reduces bone mineralization and impairs calcium and phosphorus homeostasis and is associated with obesity, type 2 diabetes, type 1 diabetes and early mortality. 25-hydroxylation of vitamin D is believed to occur only in the liver through a constitutive enzymatic process. Recent studies, however, suggest the existence of extrahepatic CYP2R1 expression, and I have recently described regulation of liver CYP2R1 expression and activity in aged and obese mice. These results raise three intriguing possibilities with important implications: 1) 25-hydroxylation is regulated, which would provide a mechanism whereby some conditions alter serum 25(OH)D independent of supply; 2) common variation in the CYP2R1 gene gives rise to heterogeneity in 25-hydroxylase activity, which would explain variation in individual supplementation response; and 3) there is physiologically relevant CYP2R1 outside the liver, thus, non-hepatic diseases may affect 25(OH)D in unpredicted, tissue-specific ways. This work will examine these possibilities. This proposal will address critical gaps in our understanding of vitamin D homeostasis, specifically the heretofore unrecognized dynamic regulation of 25-hydroxylation of vitamin D by CYP2R1, and the potential role of the testis as an auxiliary organ for production of 25(OH)D. Additionally, these studies address the unmet need to identify patients at greatest risk of developing disorders related to low 25(OH)D at an early stage using genetic profiling rather than biochemical screening. In sum, the proposed studies and training plan build on the applicants previous work, leverage an optimal infrastructure for training in vitamin D physiology and pathophysiology and bioinformatics, and offer a clear mentored path for continued transition to independent research. The proposed research will be carried out under the mentorship of Michael A. Levine, M.D. and Hakon Hakonarson M.D., Ph.D. Dr. Levine is a leader in the field of vitamin D physiology and is a professor of Pediatrics and the director of The CHOP Bone Health Center (BHC), which includes a substantial research arm. Dr. Hakonarson is a world leader in dissecting the genetic contributors to disease and is an Associate Professor of Pediatrics and the head of the Center for Applied Genomics (CAG). They have each mentored numerous successful Postdoctoral fellows. An advisory committee of talented and invested clinician-scientists has been assembled to guide career development and science. The environment of CHOP, Penn, the BHC and the CAG provides extensive resources and intellectual expertise. This is an ideal training setting to develop the skill set to continue the transition to an independent career as a physician-scientist.

 描述（由应用程序提供）：该提案描述了一项为期三年的培训计划，以开发内分泌生理学的独立研究职业。候选人是费城儿童医院（CHOP）的小儿内分泌学教练，并参加了M.D.-PH.D.在分子和细胞生物学中。他扩大了接受密集翻译研究的培训，该研究得到了儿科部露丝·柯希斯坦国家研究服务奖（T32），小儿内分泌学会（PES）研究奖学金和内分泌学会临床学者奖的支持，目前是内分泌学和糖尿病研究局（K1）的临床研究（K1）的临床研究（K1）临床研究（K1）临床研究（K1）。增强和麻醉研究基金会和PES临床学者奖。拟议的研究将增强我们对维生素D代谢和生理学的理解。维生素D不足是常见的，被认为反映了阳光依赖性的合成或维生素D的摄入。低25-羟基维生素D（钙二酚-25（OH）D）降低骨矿化，损害钙和磷稳态，并与肥胖，2型糖尿病，型二糖尿病和早期二糖尿病相关。据信，维生素D的25-羟基化仅通过组成酶过程在肝脏中发生。然而，最近的研究表明存在外膜片外CYP2R1的表达，我最近描述了老化和肥胖小鼠中肝CYP2R1表达和活性的调节。这些结果引起了三种有趣的可能性，具有重要的影响：1）25-羟基化受到调节，这将提供一种机制，在某些情况下，某些情况会改变血清25（OH）D独立于供应； 2）CYP2R1基因的常见变异导致25-羟化酶活性的异质性，这可以解释单个补充反应的变化； 3）肝脏以外有与物理相关的CYP2R1，因此，非肝病可能会以未预测的，组织特异性的方式影响25（OH）D。这项工作将研究这些可能性。在我们对维生素D稳态的理解中的关键差距，特别是迄今未识别的动态调节维生素D对维生素D的25-羟基化，以及睾丸作为生产25（OH）d的辅助器官的潜在作用。此外，这些研究解决了在早期使用遗传分析而不是生化筛查的早期阶段识别出与低25（OH）D相关的疾病风险的未满足的需求。总而言之，拟议的研究和培训计划基于申请人的先前工作，利用最佳基础设施来培训维生素D生理学和病理生理学和生物信息学，并为继续过渡到独立研究提供了明确的心理途径。拟议的研究将在M.D. Michael A. Levine和Hakon Hakonarson M.D.，Ph.D.的心态下进行。 Levine博士是维生素D生理学领域的领导者，是儿科教授和Chop Bone Health Center（BHC）的主任，其中包括一个实质性的研究部门。 Hakonarson博士是剖析疾病遗传因素的世界领导者，是儿科学副教授，也是应用基因组学中心（CAG）的负责人。他们每个人都指导了许多成功的博士后研究员。有才华和投资的临床科学家的咨询委员会已组建，以指导职业发展和科学。 Chop，Penn，BHC和CAG的环境提供了广泛的资源和知识专业知识。这是一个理想的培训环境，可以发展技能，以继续过渡到身体科学家独立职业。