IDENTIFICATION OF NOVEL PHOSPHATE REGULATORS

新型磷酸盐调节剂的鉴定

• 批准号: 7133263
• 负责人: HARALD W. JUEPPNER
• 金额: $ 26.25万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-10 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7133263
• 关键词: autosomal recessive trait; biotechnology; chromatin immunoprecipitation; clinical research; congenital skeletal disorder; family genetics; fibroblast growth factor; gene mutation; genetic screening; genetically modified animals; high throughput technology; homeostasis; human genetic material tag; human subject; hypophosphatemia; laboratory mouse; membrane transport proteins; molecular pathology; osteosclerosis; phosphates; protein structure function; renal tubular transport; single nucleotide polymorphism

DESCRIPTION (provided by applicant): Despite its demonstrated broad importance, the regulation of phosphate homeostasis remains incompletely understood. With the exception of cDNAs encoding different sodium-phosphate co-transporters, all molecules thus far known to be involved in regulating phosphate homeostasis have been identified by defining the molecular basis of different hereditary disorders in humans and mice that are characterized by an abnormal regulation of phosphate homeostasis. These studies by different groups have led to the identification of key regulators, including 1) PHEX, which is mutated in X-linked hypophosphatemia (XLH), 2) FGF23, for which gain-of-function mutations were found in autosomal dominant hypophosphatemic rickets (ADHR) and loss-of-function mutations in a form of familial tumoral calcinosis (FTC-2), and 3) GALNT3, an enzyme important for the initiation of O-linked glycosylation, for which loss-of-function mutations were identified in another familial form of tumoral calcinosis (FTC-1). Using the assay that was developed in our laboratory, loss of function mutations in either FGF23 or GALNT3 were shown to be associated with a dramatic increase in the serum concentration of C-terminal FGF23, yet normal intact FGF23 levels. These findings indicated that FGF23 requires post-translational modifications for normal intracellular processing and possibly for mediating its actions through some of the known FGF receptors that may recruit Klotho as a co-receptor. Using a positional cloning strategy, we recently identified NaPi-llc mutations as the cause of hereditary hypophosphatemic rickets with hypercalciuria (HHRH), thereby providing first evidence for the conclusion that NaPi-llc has a major role in renal phosphate handling. However, despite these advances in the identification of key regulators of phosphate homeostasis, it remains largely uncertain how and to what extent the identified proteins contribute to the regulation of phosphate homeostasis, and it is very likely that additional proteins are involved in these regulatory mechanisms. To explore the biology of phosphate homeostasis further, we now propose to identify a novel regulator of phosphate homeostasis by searching for the molecular defect leading to an autosomal recessive phosphate-wasting disorder that is associated with osteosclerosis. We mapped this disorder to chromosome 4q21, and once the disease-causing genetic mutation is known, we will begin exploring the underlying pathophysiological mechanisms leading to phosphate-wasting and osteosclerosis. Furthermore, we will determine whether the HPOS gene product has a role in the regulation of phosphate homeostasis in healthy individuals. In addition to defining a rare genetic disorder, these efforts may provide novel therapeutic approaches for the treatment of more common hypo- and hyperphosphatemic conditions that also affect bone metabolism, such as X-linked hypophosphatemia (XLH) and chronic kidney disease (CDK), respectively.

描述（由申请人提供）：尽管具有广泛的重要性，但磷酸盐稳态的调节仍未完全理解。除编码不同的磷酸钠共转运蛋白的CDNA外，迄今为止，所有分子都通过定义人类和小鼠的不同遗传性疾病的分子基础来鉴定出与磷酸盐抑制剂的异常调节表征的分子基础，从而确定了所有分子。 These studies by different groups have led to the identification of key regulators, including 1) PHEX, which is mutated in X-linked hypophosphatemia (XLH), 2) FGF23, for which gain-of-function mutations were found in autosomal dominant hypophosphatemic rickets (ADHR) and loss-of-function mutations in a form of familial tumoral calcinosis (FTC-2), and 3) GALNT3, an酶对于启动O连接的糖基化重要的酶，为此，以另一种家族性肿瘤钙化（FTC-1）形式鉴定出功能丧失突变。使用在我们实验室中开发的测定法，显示FGF23或GALNT3中功能突变的损失与C末端FGF23的血清浓度显着增加有关，但正常的完整FGF23水平。这些发现表明，FGF23需要对正常细胞内处理的翻译后修饰，以及可能通过一些已知的FGF受体介导其作用，这些FGF受体可能会募集Klotho作为共受体。使用位置克隆策略，我们最近确定了NAPI-LLC突变是遗传性下磷酸rik鼠（HHRH），从而为结论提供了NAPI-LLC在肾磷酸盐处理中具有重要作用的结论的第一个证据。然而，尽管在鉴定磷酸盐稳态的关键调节剂方面取得了这些进步，但在很大程度上不确定了如何以及在何种程度上鉴定出的蛋白质在何种程度上有助于调节磷酸盐稳态，并且很可能有其他蛋白质参与这些调节机制。为了进一步探索磷酸盐稳态的生物学，我们现在建议通过寻找一种与骨性骨膜细胞化有关的常染色体隐性隐性磷酸盐浪费疾病来识别磷酸盐稳态的新型调节剂。我们将这种疾病映射到4q21染色体上，一旦已知引起疾病的遗传突变，我们将开始探索导致磷酸盐浪费和骨硬化的潜在病理生理机制。此外，我们将确定HPOS基因产物是否在健康个体的磷酸稳态调节中起作用。除了定义罕见的遗传疾病外，这些努力还可以提供新的治疗方法，用于治疗更常见的低磷酸疾病，这也会影响骨骼代谢，例如X-连接的低磷酸盐血症（XLH）和慢性肾脏病（CDK）。