Pathogenic Mechanisms of Craniometaphyseal Dysplasia

颅骨干骺端发育不良的发病机制

基本信息

批准号：
9294024
负责人：
I-Ping Chen
金额：
$ 39.88万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9294024
关键词：
ATP2A2 Actomyosin Affect Alleles Ankylosis Binding Proteins Blindness Bone Development Bone Diseases Calcium Calcium Signaling Calmodulin Cell Size Cell membrane Cells Cephalic Child Complex Data Defect Diphosphates Disease Dominant-Negative Mutation Dysplasia Facial paralysis Future Genes Genetic Genomics Headache Hereditary Disease Human Impairment Investigation Knock-in Mouse Knockout Mice Life Methods Molecular Mouse Protein Mus Mutant Strains Mice Mutation Myosin Light Chains Nerve Neurologic Symptoms Obstruction Operative Surgical Procedures Orthologous Gene Osteoblasts Osteoclasts Osteoporosis Pathogenesis Pathogenicity Patients Phenotype Phosphorylation Phosphotransferases Proteins Public Health Pump Reporting Research Rho-associated kinase Role Signal Transduction Symptoms Testing Therapeutic Intervention Thinking Work autosomal dominant mutation base bone cell motility craniofacial deafness gain of function induced pluripotent stem cell infancy insight long bone loss of function mouse model mutant negative affect novel protein transport sulfated glycoprotein 2 therapeutic development therapy development trafficking translational study

项目摘要

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.

项目概要/摘要开发罕见遗传病的治疗方法与治疗更常见的疾病同样重要，因为许多这些患者中的一些患者患有终生衰弱和危及生命的症状，而治疗方法是有限或不存在。制定治疗干预措施的关键是了解细胞和这些疾病中发现的基因组异常的分子后果。该提案旨在确定以颅面骨增厚为特征的颅骨干骺端发育不良（CMD）的发病机制和加宽的长骨干骺端。 CMD 的发病早于婴儿期和颅面部骨在整个生命过程中逐渐变厚，这可能会给患者带来危及生命的后果。这颅孔狭窄而阻塞神经通常会导致失明、耳聋、面瘫和即使是幼儿也会出现严重头痛。迄今为止，除了重复性和高风险之外，还没有治疗 CMD 的方法手术。我们已经生成了携带 CMD 突变和人类诱导多能干细胞的小鼠模型来自 CMD 患者和健康捐赠者的细胞 (hiPSC)。成骨细胞和破骨细胞的细胞自主缺陷已经报道了 CMD 小鼠模型中的 (OC)。 OC 明显较小且功能不足在 CMD 小鼠和 CMD 患者中。我们使用 OC 来研究独特的突变效应，因为 OC 表现出最多的突变效应。 CMD 小鼠和没有 ANK 蛋白的小鼠之间存在显着差异。深入了解进行性强直基因 ANKH（人类）和 ANK（小鼠）的突变如何直系同源物）导致 CMD，提出了三个具体目标来检验中心假设，即突变 ANKH 通过降低功能性 ANKH 水平和减少 Ca2+/CaM 信号传导而导致 CMD，从而导致在有缺陷的肌动球蛋白复合物中。目标 1 将确定调节表达的机制和 CMD 突变体 ANK/ANKH 的定位。目标 2 将确定 CMD 突变体 ANK 对钙信号传导的作用在破骨细胞中。目标 3 将确定导致 CMD 肌动球蛋白复合物缺陷的机制破骨细胞。该项目的研究结果将成为未来转化研究的基础，重点开发 CMD 的治疗干预。该项目预计将对类似的调查产生重大影响罕见的遗传性骨疾病以及更好地理解 ANK/ANKH 在正常的骨骼发育及以上。