Pathogenic Mechanisms of Craniometaphyseal Dysplasia

项目摘要/摘要 开发罕见遗传病的治疗方法与治疗更常见的疾病一样重要，因为许多 这些患者中有终生虚弱和危及生命的症状，治疗是 有限的或不存在的。开发治疗干预的关键是了解细胞和 在这些疾病中发现的基因组异常的分子后果。这项提案旨在确定 以颅面骨增厚为特征的颅干骺端发育不良的发病机制 和加宽的长骨头干骺端。CMD的发病始于婴儿期和颅面部骨骼。 在一生中逐渐增厚，这可能会导致危及患者生命的后果。这个 通过缩小颅孔来阻塞神经通常会导致失明、耳聋、面瘫和 即使是年幼的孩子也会出现严重的头痛。到目前为止，除了重复和有风险的治疗外，还没有治疗CMD的方法 手术。我们已经建立了一个携带CMD突变和人类诱导的多能干细胞的小鼠模型 CMD患者和健康供者的细胞(HiPSCs)。成骨细胞和破骨细胞的细胞自主性缺陷 (OCS)在CMD小鼠模型中的作用已有报道。OCS明显较小，功能上存在缺陷 在CMD小鼠和CMD患者中。我们使用OCS来研究独特的突变效应，因为OCS显示的 CMD小鼠和不含ANK蛋白的小鼠之间存在显著差异。 为了深入了解进行性强直基因Ankh(人类)和ANK(小鼠)的突变 同源基因)导致CMD，提出了三个具体目标来检验中心假设，即 AnkH通过降低功能性AnkH水平和减少钙/CaM信号导致CMD，从而导致 在有缺陷的肌球蛋白复合体中。目标1将确定调控表达的机制和 CMD突变体ANK/Ankh的定位目标2将确定CMD突变体ANK在钙信号转导中的作用 在破骨细胞中。目标3将确定导致CMD肌动球蛋白复合体缺陷的机制 破骨细胞。该项目的发现将成为未来专注于开发的翻译研究的基础 CMD的治疗干预。该项目预计将对类似的调查产生很大影响 罕见的遗传性骨病以及对ANK/Ankh在 骨骼发育正常，甚至更高。

Project Summary/Abstract Developing therapies for rare genetic diseases is as important as for more common disorders because many of these patients are suffering from lifelong debilitating and life-threatening symptoms with treatment being limited or non-existent. The key for developing therapeutic interventions is to understand the cellular and molecular consequences of genomic abnormalities identified in these diseases. This proposal aims to identify pathogenic mechanisms of craniometaphyseal dysplasia (CMD), characterized by thickened craniofacial bones and widened metaphyses of long bones. The onset of CMD begins early in infancy and cranifacial bones progressively thicken throughout life, which can result in life-threatening consequences for patients. The obstruction of nerves by narrowing cranial foramina often leads to blindness, deafness, facial paralysis and severe headache even in young children. To date, there is no treatment for CMD other than repetitive and risky surgeries. We have generated a mouse model carrying a CMD mutation and human induced pluripotent stem cells (hiPSCs) from CMD patients and healthy donors. Cell-autonomous defects in osteoblasts and osteoclasts (OCs) in a mouse model for CMD have been reported. OCs are significantly smaller and functioanlly deficient in CMD mice and CMD patients. We use OCs to study unique mutational effects because OCs show the most notable differences between CMD mice and mice that have no ANK protein. To gain insight into how mutations in the progressive ankylosis gene ANKH (human) and ANK (mouse orthologue) cause CMD, three Specific Aims are proposed to test the central hypothesis that mutations in ANKH cause CMD by reducing levels of functional ANKH and by decreasing Ca2+/CaM signaling, which results in defective actomyosin complexes. Aim 1 will determine the mechanisms regulating expression and localization of CMD mutant ANK/ANKH. Aim 2 will determine the role of CMD mutant ANK on calcium signaling in osteoclasts. Aim 3 will identify the mechanisms leading to defective actomyosin complexes in CMD osteoclasts. Findings from this project will be the basis for a future translational study to focus on developing therapeutic interventions for CMD. This project is expected to have a high impact on investigations of similar rare genetic bone disorders as well as on a better understanding of unrecognized roles of ANK/ANKH in normal bone development and beyond.