NIAMS: CORT

描述（由申请人提供）：耶鲁大学研究翻译中心（CORT）致力于改善X相关低磷血症佝偻病（XLH）患者的护理。XLH是美国最常见的遗传性佝偻病，是该CORT的理想焦点。尽管如此，治疗是次优的，患者背负着显著的骨骼发病率。最近对XLH的研究发现了一个新的、重要的由部分成纤维细胞生长因子受体调节的磷酸盐(P)稳态系统。PI和他的合作者为改善XLH患者的护理以及我们对这种疾病发病机制的理解做出了重要贡献。我们在这种疾病方面的专业知识通过三个拟议项目的范围得到了证明，这些项目真正跨越了病床到病床。项目3为我们将新发现带到临床的能力提供了切实的证据。我们的科学目标是鉴定和验证XLH中骨骼疾病的介质。项目1将确定血清PTH、FGF23或P是否能通过综合XLH疾病指数预测疾病严重程度。甲状旁腺功能亢进是XLH的主要问题。患有这种并发症的患者将参加一项临床试验，以确定纠正甲状旁腺功能亢进是否能改善骨骼疾病。项目2研究了我们关于P调节软骨细胞凋亡的新发现，并将表征软骨细胞P转运蛋白及其通过PTH、FGF23和维生素d的调节。项目3将鉴定和表征FGF23受体。基于这些发现，我们将开发FGF23受体激活的小分子抑制剂，并在Hyp小鼠（XLH的小鼠同源物）中验证其功效。这三个项目将相互影响，并直接相互通知。我们希望鉴定软骨细胞凋亡（P2）的调节因子将有助于关注P1的生物标志物的临床研究。对P3中FGF受体的鉴定将有助于对P2中FGF通路的靶向研究。FGF23抑制剂P3的成功鉴定将为P1研究的XLH队列的未来1期临床试验提供主要证据。所有的项目都将得到研究核心的支持。CORT系列研讨会和试点研究计划将更好地向耶鲁生物医学研究界介绍XLH，并在我们的研究基地促进新的研究。最重要的是，CORT将为耶鲁大学和更广泛的生物医学学术界提供一个成功的转化研究工作模式。

DESCRIPTION (provided by applicant): The Yale Center of Research Translation (CORT) is dedicated to improving the care of patients with X linked hypophosphatemic rickets (XLH). XLH is the most common form of inherited rickets in the US and is an ideal focus for this CORT. Despite this, therapy is suboptimal and patients are burdened with significant skeletal morbidity. Recently the study of XLH has led to the identification of a novel and important phosphate (P) homeostatic system regulated in part fibroblast growth factor receptor(s). The PI and his collaborators have made important contributions to improving the care of patients with XLH as well as to our understanding of the pathogenesis of this disorder. Our expertise in this disease is demonstrated by the scope of the three proposed projects, which truly span the bedside to the bench. Project 3 provides tangible evidence of our ability to bring new discoveries to the clinic. Our scientific goal is to identify and validate mediators of skeletal disease in XLH. Project 1 will determine whether serum PTH, FGF23, or P best predict disease severity as measured by a comprehensive XLH disease index. Hyperparathyroidism is a major problem in XLH. Patients with this complication will participate in a clinical trial to determine if correcting hyperparathyroidism improves skeletal disease. Project 2 pursues our new discovery that P regulates chondrocyte apoptosis and will characterize chondrocyte P transporters and their regulation by PTH, FGF23, and vitamin D. Project 3 will identify and characterize FGF23 receptor(s). Based on these findings we will develop small molecule inhibitors of FGF23 receptor activation and demonstrate their efficacy in Hyp mice, the murine homolog of XLH. The 3 projects will interact and directly inform one another. We expect that identification of regulators of chondrocyte apoptosis (P2) will help focus the clinical investigation of biomarkers in P1. The identification of the FGF receptor in P3 will allow targeted studies of the FGF pathway in P2. The successful identification of an FGF23 inhibitor P3 will provide proof of principal for future Phase 1 clinical trials in the XLH cohort studied in P1. All projects will be supported by the Research Core. The CORT seminar series and pilot study program will better inform the Yale biomedical research community about XLH and foster new research in our Research Base. Most importantly the CORT will provide a successful working model of translational research for Yale and the wider biomedical academic community.