NIAMS: CORT

尼亚姆斯：科特

• 批准号: 7672905
• 负责人: THOMAS O CARPENTER
• 金额: --
• 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/7672905
• 关键词: Address; Adult; Affect; Animal Model; Animals; Apoptosis; Area; Arthritis; Award; Basic Science; Biological; Biological Markers; Biology; Biomedical Research; Bone Pain; Boston; Cardiac; Caring; Chondrocytes; Chronic; Clinic; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Commit; Communication; Communities; Complement; Complication; Computer Systems Development; Craniosynostosis; Data; Deformity; Development; Dihydroxycholecalciferols; Discipline; Disease; Disease Pathway; Elements; Ensure; Environment; Epiphysial cartilage; Exostoses; FGF7 gene; Faculty; Familial hypophosphatemic bone disease; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Fostering; Fracture Healing; Functional disorder; Funding; Future; Genotype; Goals; Growth; Healed; Heart; Homeostasis; Homologous Gene; Human; Hyperparathyroidism; Hypophosphatemia; Impairment; Incidence; Individual; Inherited; Institutes; Institution; International; Ions; Kidney; Knowledge; Laboratories; Lesion; Link; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Metabolism; Minerals; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Musculoskeletal; Musculoskeletal Diseases; Mutation; Oncogenic; Operative Surgical Procedures; Osteomalacia; Outcome; Parathyroid Hormones; Pathogenesis; Pathology; Pathway interactions; Patient Care; Patients; Phase; Phase I Clinical Trials; Phenotype; Physiological; Pilot Projects; Play; Prevalence; Process; Publications; Qualifying; Receptor Activation; Receptor Signaling; Recording of previous events; Regulation; Relative (related person); Reporting; Research; Research Infrastructure; Research Personnel; Research Project Grants; Rickets; Role; Science; Series; Serum; Serum Phosphorus Level; Severity of illness; Signal Transduction; Skeletal system; Standards of Weights and Measures; Stimulus; Structure; Sum; Support Groups; Support of Research; System; TNFRSF5 gene; Technical Expertise; Therapeutic; Therapeutic Intervention; Time; Tooth Loss; Training; Translational Research; Translations; Treatment Efficacy; United States National Institutes of Health; Universities; Update; Upper arm; Vitamin D; Work; advocacy organizations; base; bench to bedside; bone; calcification; concept; design; healing; human PTH protein; improved; indexing; inhibitor/antagonist; inorganic phosphate; insight; interest; keratinocyte growth factor; lead phosphate; long bone; member; mouse model; multidisciplinary; novel; novel therapeutics; programs; receptor; skeletal disorder; small molecule; soft tissue; sound; wasting

The Yale Center of Research Translation (CORT) is dedicated to improving the care of patients with Xlinked 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.

耶鲁大学研究翻译中心 (CORT) 致力于改善 Xlinked 患者的护理 低磷血症性佝偻病（XLH）。 XLH 是美国最常见的遗传性佝偻病， 这个 CORT 的理想焦点。尽管如此，治疗仍不理想，患者承受着严重的负担 骨骼发病率。最近，XLH 的研究发现了一种新颖且重要的物质。 磷酸盐 (P) 稳态系统部分受成纤维细胞生长因子受体调节。 PI 和他的 合作者为改善 XLH 患者的护理以及我们的工作做出了重要贡献 了解这种疾病的发病机制。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，真正跨越床边到工作台。项目3提供了有形的 我们有能力将新发现带入临床的证据。我们的科学目标是识别和验证 XLH 中骨骼疾病的介质。项目 1 将确定血清 PTH、FGF23 或 P 是否最好预测 通过综合 XLH 疾病指数衡量的疾病严重程度。甲状旁腺功能亢进症是一个主要 XLH 中的问题。患有这种并发症的患者将参加临床试验以确定是否可以纠正 甲状旁腺功能亢进症可改善骨骼疾病。项目 2 追求 P 调节的新发现 软骨细胞凋亡，并表征软骨细胞 P 转运蛋白及其受 PTH 的调节， FGF23 和维生素 D。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证明其在Hyp中的功效 小鼠，XLH 的鼠同源物。这三个项目将相互作用并直接相互通报。我们期望 软骨细胞凋亡（P2）调节因子的鉴定将有助于集中临床研究 P1 中的生物标志物。 P3 中 FGF 受体的鉴定将有助于对 FGF 通路进行针对性研究 在P2中。 FGF23抑制剂P3的成功鉴定将为未来第一阶段提供原理证明 P1 中研究的 XLH 队列的临床试验。所有项目都将得到研究核心的支持。这 CORT 研讨会系列和试点研究计划将更好地为耶鲁生物医学研究界提供信息 关于 XLH 并在我们的研究基地促进新的研究。最重要的是 CORT 将提供 耶鲁大学和更广泛的生物医学学术界成功的转化研究工作模式。