Family with Sequence Similarity 20, Member C (FAM20C) and Brain Calcification

具有序列相似性 20 的家族,成员 C (FAM20C) 和脑钙化

基本信息

  • 批准号:
    10217493
  • 负责人:
  • 金额:
    $ 15.15万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-05-01 至 2024-09-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Brain calcification is a common neuroimaging finding in individuals with a variety of hereditary or nonhereditary syndromes or many other acquired medical conditions. Raine syndrome, a rare autosomal recessive disease, is caused by mutations in the Family with sequence similarity 20, member C (FAM20C) gene. It is characterized by skeletal and dental defects along with brain calcification. Mouse genetic studies have shown that Sox2- cre;Fam20cfl/fl mice, in which Fam20c was deleted in nearly all the body tissues and cells, developed hypophosphatemic rickets/osteomalacia as well as dental abnormalities. FAM20C encodes a Golgi-localized protein kinase that phosphorylates secretory proteins, including osteopontin (OPN) and matrix extracellular phosphoglycoprotein (MEPE) – two members of the Small Integrin-Binding LIgand N-linked Glycoprotein (SIBLING) family. Both OPN and MEPE contain an acidic serine- and aspartate-rich motif (ASARM). Previous studies have demonstrated that OPN and the ASARM peptides derived from OPN and MEPE proteins inhibit mineralization, and such inhibitory effects depend on the extent of their phosphorylation. While significant progresses have been made in understanding the functions of FAM20C in osteogenesis and odontogenesis, the pathogenic mechanisms underlying the brain calcification in Raine syndrome patients remain largely unknown. More recently, the principal investigator (PI) have found that 1) Fam20c is widely expressed in the mouse brain; 2) Sox2-cre;Fam20cfl/fl mice develop apparent brain calcification by the age of postnatal 3 months; and 3) osteopontin (Opn), a member of SIBLING family, is expressed in the mouse brain neurons. These new findings together with the previous findings on FAM20C and the SIBLING proteins lead to the novel hypothesis that the loss of FAM20C function in the brain cells causes the failure of phosphorylation of OPN and MEPE proteins, resulting in brain calcification. Two specific aims are proposed to test this hypothesis: Aim 1 is to determine if the calcification is associated with the loss of FAM20C function in the brain in Sox2-cre;Fam20cfl/fl mice. To complete this aim, the PI will map the locations of the brain calcifications in Sox2-cre;Fam20cfl/fl mice with age and correlate the calcifications with the loss of FAM20C function in each brain structure. Aim 2 is to determine if OPN and MEPE are phosphorylated in the brain tissues of the control mice, and if the phosphorylation of these two proteins is lost in Sox2-cre;Fam20cfl/fl mice. To fulfill this aim, the PI will isolate OPN and MEPE proteins from the brain tissues of Fam20cfl/fl (control) and Sox2-cre;Fam20cfl/fl mice, and then determine and compare the overall phosphorylation levels and phosphorylation sites of these two proteins between Fam20cfl/fl and Sox2-cre;Fam20cfl/fl mice. Successful completion of the proposed studies will provide new insights into our understanding of how ectopic calcification is prevented in the brain.
项目概要 脑钙化是患有各种遗传性或非遗传性的个体的常见神经影像学发现 综合症或许多其他后天获得的疾病。雷恩综合征是一种罕见的常染色体隐性遗传病, 由具有序列相似性的家族 20 成员 C (FAM20C) 基因的突变引起。它的特点是 由骨骼和牙齿缺陷以及大脑钙化引起。小鼠遗传学研究表明 Sox2- cre;Fam20cfl/fl 小鼠,其中几乎所有身体组织和细胞中的 Fam20c 均被删除 低磷血症佝偻病/骨软化症以及牙齿异常。 FAM20C 编码高尔基体定位 磷酸化分泌蛋白的蛋白激酶,包括骨桥蛋白 (OPN) 和细胞外基质 磷酸糖蛋白 (MEPE) – 小整合素结合配体和 N 连接糖蛋白的两个成员 (兄弟姐妹)家庭。 OPN 和 MEPE 均含有富含丝氨酸和天冬氨酸的酸性基序 (ASARM)。以前的 研究表明,OPN 以及源自 OPN 和 MEPE 蛋白的 ASARM 肽可抑制 矿化作用,这种抑制作用取决于其磷酸化的程度。虽然意义重大 在了解 FAM20C 在成骨和牙发育中的功能方面已取得进展, 雷恩综合征患者大脑钙化的致病机制仍然很大程度上未知。 最近,首席研究员 (PI) 发现 1) Fam20c 在小鼠大脑中广泛表达; 2) Sox2-cre;Fam20cfl/fl小鼠在出生后3个月时出现明显的脑钙化;和 3) 骨桥蛋白 (Opn) 是 SIBLING 家族的成员,在小鼠大脑神经元中表达。这些新发现 结合之前对 FAM20C 和 SIBLING 蛋白的发现,得出了一个新的假设: 脑细胞中 FAM20C 功能丧失导致 OPN 和 MEPE 磷酸化失败 蛋白质,导致大脑钙化。提出了两个具体目标来检验这一假设: 目标 1 是 确定 Sox2-cre 中钙化是否与大脑中 FAM20C 功能丧失有关;Fam20cfl/fl 老鼠。为了完成这一目标,PI 将绘制 Sox2-cre;Fam20cfl/fl 小鼠大脑钙化的位置图 随着年龄的增长,并将钙化与每个大脑结构中 FAM20C 功能的丧失联系起来。目标 2 是 确定 OPN 和 MEPE 在对照小鼠的脑组织中是否被磷酸化,以及是否 Sox2-cre;Fam20cfl/fl 小鼠中这两种蛋白的磷酸化消失。为了实现这一目标,PI 将隔离 来自 Fam20cfl/fl(对照)和 Sox2-cre;Fam20cfl/fl 小鼠脑组织的 OPN 和 MEPE 蛋白,然后 确定并比较这两种蛋白质的总体磷酸化水平和磷酸化位点 Fam20cfl/fl 和 Sox2-cre 之间;Fam20cfl/fl 小鼠。成功完成拟议的研究将提供 对我们如何预防大脑异位钙化的理解有了新的见解。

项目成果

期刊论文数量(1)
专著数量(0)
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Hua Zhang其他文献

Hua Zhang的其他文献

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{{ truncateString('Hua Zhang', 18)}}的其他基金

Targeting the Pial Collateral Circulation for Mitigation of Cerebral Ischemia
针对软脑膜侧支循环缓解脑缺血
  • 批准号:
    10376751
  • 财政年份:
    2013
  • 资助金额:
    $ 15.15万
  • 项目类别:
Targeting the Pial Collateral Circulation for Mitigation of Cerebral Ischemia
针对软脑膜侧支循环缓解脑缺血
  • 批准号:
    10596512
  • 财政年份:
    2013
  • 资助金额:
    $ 15.15万
  • 项目类别:

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