NIAMS: CORT

耶鲁大学翻译研究中心(CORT)致力于改善X连锁低磷血症(XLH)患者的护理。XLH是美国最常见的遗传性软骨病，也是CORT的理想治疗对象。尽管如此，治疗是次优的，患者背负着严重的骨骼发病率。最近，对XLH的研究发现了一个新的、重要的磷酸(P)动态平衡系统，该系统由部分成纤维细胞生长因子受体(S)调控。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的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证明，这些项目真正跨越了从床边到替补席的范围。项目3提供了切实的证据，证明我们有能力将新发现带到临床上。我们的科学目标是确定和验证XLH骨骼疾病的介体。项目1将确定血清PTH、FGF23或P中哪一个最能预测疾病的严重程度，通过综合的XLH疾病指数来衡量。甲状旁腺机能亢进是XLH的一个主要问题。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症是否可以改善骨骼疾病。项目2将继续我们的新发现，即P调节软骨细胞的凋亡，并将表征软骨细胞P转运蛋白以及甲状旁腺素、成纤维细胞生长因子23和维生素D对其调节作用。项目3将鉴定和表征成纤维细胞生长因子23受体(S)。基于这些发现，我们将开发FGF23受体激活的小分子抑制剂，并证明它们在Hyp小鼠身上的疗效，Hyp小鼠是XLH的小鼠同源物。这3个项目将相互作用，并直接相互通报。我们期望对软骨细胞凋亡调节因子(P2)的识别将有助于集中对P1中的生物标记物进行临床研究。P3中成纤维细胞生长因子受体的鉴定将使对P2中成纤维细胞生长因子途径的靶向研究成为可能。FGF23抑制剂P3的成功鉴定将为在P1研究的XLH队列中进行未来的1期临床试验提供原则证据。所有项目都将得到研究核心的支持。CORT系列研讨会和先导研究计划将更好地向耶鲁生物医学研究社区通报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。

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.