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

 描述(由申请人提供)：本提案描述了一项为期三年的培训计划，旨在发展内分泌生理学的独立研究生涯。应聘者是费城儿童医院(CHOP)的儿科内分泌学讲师和主治医师，拥有分子和细胞生物学的医学博士学位。他继续接受培训，从事密集的翻译研究，获得了儿科Ruth 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，目前获得了儿科糖尿病研究(K12)内分泌科和糖尿病部门职业发展奖，该奖项是由临床实践改进和麻醉研究基金会颁发的职业发展奖和PES临床学者奖。这项拟议的研究将加深我们对维生素D代谢和生理学的理解。维生素D不足很常见，被认为是对阳光依赖的维生素D合成或摄取不足的反映。低25-羟基维生素D(钙二醇-25(OH)D)减少骨骼矿化，破坏钙和磷的动态平衡，并与肥胖、2型糖尿病、1型糖尿病和早期死亡有关。维生素D的25-羟基化被认为只发生在肝脏中，通过一个结构性的酶过程。然而，最近的研究表明，肝脏外存在CYP2R1的表达，我最近描述了老年和肥胖小鼠肝脏CYP2R1的表达和活性的调节。这些结果提出了三种有趣的具有重要意义的可能性：1)25-羟化被调节，这将提供一种机制，使某些条件改变血清25(OH)D不依赖于供应；2)CYP2R1基因的常见变异导致25-羟基酶活性的异质性，这可以解释个体补充反应的差异；以及3)在肝脏之外存在生理上相关的CYP2R1，因此，非肝病可能以不可预测的、组织特有的方式影响25(OH)D。这项工作将研究这些可能性。这项建议将解决我们在理解维生素D稳态方面的关键空白，特别是迄今为止未知的由CYP2R1动态调节维生素D的25-羟基化，以及睾丸作为产生25(OH)D的辅助器官的潜在作用。此外，这些研究解决了未得到满足的需求，即使用遗传图谱而不是生化筛查，在早期阶段识别与低25(OH)D相关的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工作的基础上，利用维生素D生理学、病理生理学和生物信息学方面的最佳培训基础设施，并为继续向独立研究过渡提供了一条明确的指导路径。这项拟议的研究将在Michael A.Levine医学博士和Hakon Hakonarson医学博士的指导下进行。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。哈科纳森博士是剖析致病基因的世界领先者，也是儿科学副教授和应用基因组学中心(CAG)的负责人。他们每个人都指导过许多成功的博士后研究员。一个由有才华和有投资的临床医生和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、宾夕法尼亚大学、BHC和CAG的环境提供了广泛的资源和智力专业知识。这是一个理想的培训环境，以发展技能集，继续过渡到独立的职业生涯，作为一名内科科学家。

 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.