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Control of Bone Formation in Craniometaphyseal Dysplasia

颅骨干骺端发育不良中骨形成的控制

基本信息

批准号：
8628830
负责人：
ERNST J REICHENBERGER
金额：
$ 36.58万
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：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8628830
关键词：
Actins Affect Albers-Schonberg disease Animal Model Ankylosis Auditory Bone Diseases Bone Marrow Transplantation Bone Matrix Bone Resorption Bone remodeling Caliber Calvaria Cells Cephalic Characteristics Conductive hearing loss Cytoskeleton Diet Diphosphates Disease Dissection Dysplasia Environment Equilibrium Extracellular Matrix Facial paralysis Flare Functional disorder Future Gene Expression Regulation Genes Genetic Goals Homeostasis Human Hydroxyapatites Hyperostosis Impairment In Vitro Integral Membrane Protein Intracellular Transport Knock-in Mouse Knockout Mice Lead Metaphysis Minerals Modeling Molecular Mus Mutation Neurons Nodule Operative Surgical Procedures Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis Pathogenesis Patients Phenotype Phenylalanine Physiologic calcification Population Publishing Rare Diseases Regulation Role Serum Staging Testing Therapeutic Intervention Transgenic Mice Visual bone bone cell bone mass cell type craniofacial extracellular face bone structure gain of function homologous recombination in vivo in vivo Model inhibitor/antagonist inorganic phosphate long bone loss of function middle ear mineralization mouse model mutant novel therapeutic intervention osteoblast differentiation promoter public health relevance research study skeletal

项目摘要

DESCRIPTION (provided by applicant): Craniometaphyseal dysplasia (CMD) is a rare genetic bone disorder, which results in hyperostosis of craniofacial bones and flaring of metaphyses in long bones. We have created an animal model for this orphan disease by introducing one of the most common CMD mutations, a Phe377 deletion, into the mouse Ank gene by homologous recombination. ANK is a transmembrane protein known to transport intracellular pyrophosphate (PPi) into the extracellular environment. PPi is an important regulator of mineralization in bone. Ank Phe377del knock-in mice develop hyperostotic cranial and facial bone, reduced diameters of cranial foramina and undertrabeculated widened metaphyses, thus expressing the skeletal hallmarks of CMD. In this application, we propose 1) to study the role of phosphate and pyrophosphate in the hypomineralization phenotype of the AnkKI/KI mouse model and 2) to investigate direct effects of the ANK Phe377del mutation on gene regulation of specific differentiation stages during osteoblastogenesis. 3) We will investigate the contribution of osteoclasts to the bone mass phenotype of AnkKI/KI mice. Our long-term goal is to study molecular control mechanisms that regulate bone formation and bone remodeling in patients with CMD or similar craniotubular conditions. This Ank Phe377del knock-in model is the first to fully replicate the CMD phenotype enabling us to study the pathophysiology of CMD in an in vivo model. These studies will have broad impact on our understanding of bone homeostasis and are expected to impact future treatment of CMD and related disorders. A better understanding of mechanisms for bone mineralization and control of bone mass is important for large segments of the population who suffer from imbalance of bone formation and resorption, including patients with osteoporosis and osteopetrosis.

描述（由申请人提供）：颅骨干骺端发育不良（CMD）是一种罕见的遗传性骨病，导致颅面骨骨质增生和长骨干骺端张开。我们通过同源重组将最常见的 CMD 突变之一（Phe377 缺失）引入小鼠 Ank 基因，创建了这种罕见疾病的动物模型。 ANK 是一种跨膜蛋白，已知可将细胞内焦磷酸盐 (PPi) 转运至细胞外环境。 PPi 是骨矿化的重要调节剂。 Ank Phe377del 敲入小鼠出现颅骨和面骨骨质增生、颅孔直径减小以及小梁下干骺端变宽，从而表达 CMD 的骨骼特征。在本申请中，我们建议 1) 研究磷酸盐和焦磷酸盐在 AnkKI/KI 小鼠模型低矿化表型中的作用，2) 研究 ANK Phe377del 突变对成骨细胞生成过程中特定分化阶段基因调控的直接影响。 3）我们将研究破骨细胞对AnkKI/KI小鼠骨量表型的贡献。我们的长期目标是研究调节 CMD 或类似颅管疾病患者骨形成和骨重塑的分子控制机制。这个 Ank Phe377del 敲入模型是第一个完全复制 CMD 表型的模型，使我们能够在体内模型中研究 CMD 的病理生理学。这些研究将对我们对骨稳态的理解产生广泛影响，并有望影响 CMD 和相关疾病的未来治疗。更好地了解骨矿化和骨量控制的机制对于大部分患有骨形成和吸收不平衡的人群（包括骨质疏松症和骨石症患者）非常重要。