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

 描述（由申请人提供）：本提案描述了一个为期三年的培训计划，以发展内分泌生理学的独立研究生涯。候选人是费城儿童医院（CHOP）的儿科内分泌学讲师和主治医师，拥有医学博士学位。博士在分子和细胞生物学中。他扩展了他的培训，从事密集的转化研究，由儿科部门的露丝L。Kirschstein国家研究服务奖（T32），儿科内分泌学会（PES）研究奖学金和内分泌学会临床学者奖，目前由儿科糖尿病研究（K12）内分泌学和糖尿病职业发展奖部门支持，临床实践增强和麻醉研究基金会的职业发展奖和PES临床学者奖。这项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，被认为反映了缺乏阳光依赖性合成或摄入维生素D。低25-羟基维生素D（骨化二醇-25（OH）D）降低骨矿化，损害钙和磷稳态，并与肥胖，2型糖尿病，1型糖尿病和早期死亡率有关。25-维生素D的羟基化被认为仅在肝脏中通过组成性酶促过程发生。然而，最近的研究表明存在肝外CYP 2 R1表达，我最近描述了老年和肥胖小鼠肝脏CYP 2 R1表达和活性的调节。这些结果提出了三种有趣的可能性：1）25-羟化是受调节的，这可能提供了一种机制，使某些条件改变血清25（OH）D，而不依赖于供应：2）CYP 2 R1基因的常见变异引起25-羟化酶活性的异质性，这可能解释个体补充反应的差异;和3）在肝脏外存在生理相关的CYP 2 R1，因此，非肝脏疾病可能以不可预测的组织特异性方式影响25（OH）D。这项工作将研究这些可能性。该提案将解决我们对维生素D稳态的理解中的关键空白，特别是迄今未被认识到的CYP 2 R1对维生素D 25-羟基化的动态调节，以及睾丸作为生产25（OH）D的辅助器官的潜在作用。此外，这些研究解决了未满足的需求，即在早期阶段使用遗传分析而不是生化筛查来识别患有低25（OH）D相关疾病的风险最大的患者。总之，拟议的研究和培训计划建立在申请人以前的工作基础上，利用维生素D生理学和病理生理学以及生物信息学培训的最佳基础设施，并为继续过渡到独立研究提供明确的指导路径。拟议的研究将在Michael A. Levine，医学博士和Hakon Hakonarson医学博士博士Levine博士是维生素D生理学领域的领导者，也是儿科学教授和CHOP骨健康中心（BHC）的主任，该中心包括一个重要的研究部门。Hakonarson博士是解剖疾病遗传因素的世界领导者，也是儿科学副教授和应用基因组学中心（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。一个由有才华和投资的临床科学家组成的咨询委员会已经成立，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长。这是一个理想的培训环境，以发展技能，继续过渡到一个独立的职业生涯作为一个医生，科学家。

 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.