Advancing Product Development for Hypoparathyroidism: A Prospective Natural History Study of the Clinical Outcomes and Regulation of Disordered Mineral Metabolism

推进甲状旁腺功能减退症的产品开发：对矿物质代谢紊乱的临床结果和调节的前瞻性自然历史研究

• 批准号: 10573824
• 负责人: THOMAS L. NICKOLAS
• 金额: $ 39.99万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-08-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573824
• 关键词: Advancing; Product; Development; Hypoparathyroidism; Prospective

Hypoparathyroidism (HPT) is a rare disorder characterized by low parathyroid hormone (PTH) and calcium levels. Patients suffer consequences of hypocalcemia, including paresthesias, arrhythmias, and seizures. Conventional treatment to prevent these life-threatening events is calcium and active vitamin D. However, complications of HPT, including kidney and cardiovascular disease, cataracts, basal ganglia calcifications and neuropsychiatric disorders, occur despite, and possibly due to, conventional treatment. Although we found increased bone calcification may be beneficial to the skeleton, calcification of end-organs may be fully or partially responsible for these complications. Registry, retrospective, and claims studies have reported vascular calcifications in HPT patients; we noted brain calcifications, and observational data document coronary artery calcifications. Other HPT-associated metabolic derangements may also be contributory. Unfortunately, the pathogenesis, epidemiology, natural history, and links between HPT, end-organ diseases, vascular calcifications, and other derangements are unclear. This represents a significant scientific gap and impedes the: (1) diagnosis, monitoring, mitigation, and prevention of HPT associated complications; (2) development, study, and implementation of new strategies to prevent HPT-associated end-organ damage; and (3) ability to conduct studies leading to advances in the HPT treatment paradigm. These gaps are particularly relevant in light of PTH treatment, a developing off-label therapeutic for HPT. PTH treatment had pro-calcific side effects reported in FDA registry trials for osteoporosis and its possible role in calcification and end-organ diseases in HPT are not clear. Indeed, although studies reported that HPT managed with conventional treatment was associated with kidney function decline, we found that kidney function did not decline in patients managed with PTH instead of conventional therapy. Also, our data suggest a link between altered bone gene expression and dysregulation of calcium. We identified circulating microRNAs highly associated with low bone turnover, a major risk factor for extra-skeletal calcification. Data suggest these same miRs may be involved in vascular calcification development. This application will provide a rigorous standardized approach to longitudinal data collection in HPT on end-organ damage and calcification propensity. Our central hypothesis is that a natural history cohort of HPT enables the study of end-organ complications. We also hypothesize that end-organ disease is related to calcification propensity and severity. The Aims are to: 1) Build a prospective cohort of longitudinally followed HPT patients to study the epidemiology and clinical impact of end-organ damage; 2). Determine the organ- specific physiologic consequences of HPT; 3). Elucidate determinants of HPT-associated end-organ damage from biochemical testing and calcification imaging. For the first time, prospective natural history data in this rare disease will define a dynamic model of HPT-associated end-organ damage. Thus, the data will be critical to inform development, study, and implementation of strategies to mitigate HPT-associated co-morbidities.

甲状腺功能减退症（HPT）是一种罕见的疾病，其特征是低甲状旁腺激素（PTH）和钙 水平。患者遭受低钙血症的后果，包括异常心理，心律不齐和癫痫发作。 防止这些威胁生命的事件的常规治疗是钙和活性维生素D。但是， HPT的并发症，包括肾脏和心血管疾病，白内障，基底神经节钙化和 尽管并且可能是由于常规治疗，但神经精神疾病仍发生。虽然我们发现 骨骼钙化增加可能对骨骼有益，末端孔的钙化可能是完全或部分的 负责这些并发症。注册表，回顾性和主张研究报告了血管 HPT患者的钙化；我们注意到大脑钙化和观察数据文件冠状动脉 钙化。其他与HPT相关的代谢紊乱也可能是贡献。不幸的是， 发病机理，流行病学，自然历史以及HPT，最终器官疾病，血管之间的联系 钙化和其他紊乱尚不清楚。这代表了一个很大的科学差距，并阻碍了： （1）诊断，监测，缓解和预防HPT相关并发症； （2）发展，研究， 并实施新的策略，以防止与HPT相关的最终器官损害； （3）能力 研究导致HPT治疗范式的进步。根据PTH，这些差距特别相关 治疗，一种发育中的HPT标签外治疗。 PTH治疗在 FDA骨质疏松症及其在HPT中的钙化和最终器官疾病中的作用不是 清除。确实，尽管研究报告说，HPT进行了常规治疗的管理与 肾功能下降，我们发现用PTH管理的患者肾功能没有下降 常规疗法。另外，我们的数据表明，骨基因表达改变与失调之间的联系 钙。我们确定了与低骨转换高度相关的循环microRNA，这是一个主要风险因素 骨骼外钙化。数据表明这些相同的miR可能参与血管钙化 发展。本应用程序将为纵向数据收集提供严格的标准化方法 HPT在末端损伤和钙化倾向上。我们的中心假设是自然历史队列 HPT可以研究最终器官并发症。我们还假设最终器官疾病与 钙化倾向和严重程度。目的是：1）建立一个前瞻性纵向队列 HPT患者研究最终器官损伤的流行病学和临床影响； 2）。确定器官 HPT的特定生理后果； 3）。阐明与HPT相关的最终器官损伤的决定因素 来自生化测试和钙化成像。这是这个罕见的前瞻性自然历史数据 疾病将定义与HPT相关的最终器官损伤的动态模型。因此，数据对于 为减轻HPT相关的合并症的策略提供开发，研究和实施。