NIAMS: CORT

尼亚姆斯：科特

• 批准号: 7485018
• 负责人: THOMAS O CARPENTER
• 金额: $ 158.99万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485018
• 关键词: NIAMS; CORT

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.

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链接下降磷酸盐rick（XLH）患者的护理。 XLH是美国遗传的最常见形式，它是该科特的理想重点。尽管如此，治疗是次优的，患者承受着明显的骨骼发病率。最近，对XLH的研究导致鉴定了由成纤维细胞生长因子受体调节的新型和重要的磷酸盐（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的发病机理的理解做出了重要贡献。我们在这种疾病方面的专业知识是通过三个拟议项目的范围来证明的，这些项目真正跨越了床边。项目3提供了我们将新发现带入诊所的能力的切实证据。我们的科学目标是识别和验证XLH中骨骼疾病的介体。项目1将确定血清PTH，FGF23或P是否可以最好地预测通过综合XLH疾病指数衡量的疾病严重程度。甲状旁腺功能亢进是XLH的主要问题。这种并发症患者将参加临床试验，以确定纠正甲状旁腺功能亢进是否可以改善骨骼疾病。项目2追求我们的新发现，即P调节软骨细胞凋亡，并将表征软骨细胞P转运蛋白及其对PTH，FGF23和VITAMIND的调节。项目3将识别并表征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，并证明它们在催眠小鼠（XLH的鼠同源物）中的疗效。这3个项目将互动并直接通知彼此。我们预计，鉴定软骨细胞凋亡的调节剂（P2）将有助于集中在P1中生物标志物的临床研究。 P3中FGF受体的鉴定将允许对P2中FGF途径的有针对性研究。 FGF23抑制剂P3的成功鉴定将为P1研究的XLH队列中的未来1期临床试验提供本金证明。所有项目都将得到研究核心的支持。 Cort研讨会系列和试点研究计划将更好地为耶鲁大学生物医学研究社区提供有关XLH的信息，并在我们的研究基础上培养新的研究。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成功的转化研究工作模型。