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：
8249380
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/8249380
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 Orphan Disease Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis Pathogenesis Patients Phenotype Phenylalanine Physiologic calcification Population Publishing 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. PUBLIC HEALTH RELEVANCE: The questions we ask in this application seek to understand the consequences of the CMD mutation on bone remodeling and to investigate mechanisms that lead to the CMD-like phenotype in our Ank knock-in mouse model. We expect that understanding mechanisms that lead to CMD will help to develop strategies for therapeutic intervention for this debilitating disorder. We also expect a broad impact on the field of bone remodeling as the mutation in this animal model affects some key mechanisms for bone mineralization and regulation of bone cells.

描述（由申请人提供）：颅底截骨性发育不良（CMD）是一种罕见的遗传骨疾病，导致颅面骨骼的骨化和长骨中的形而上学的膨胀。我们通过通过同源重组将最常见的CMD突变（PHE377缺失）引入小鼠ANK基因，为这种孤儿疾病创建了动物模型。 ANK是一种已知将细胞内焦磷酸（PPI）转移到细胞外环境中的跨膜蛋白。 PPI是骨骼中矿化的重要调节剂。 ANK PHE377DEL敲入小鼠会形成骨化颅骨和面部骨骼，颅孔直径降低，而被捕量较少，从而表达了CMD的骨骼标志。在此应用中，我们建议1）研究磷酸盐和焦磷酸盐在ANKKI/KI小鼠模型的低矿化表型中的作用，而2）研究ANK PHE377DEL突变对骨基细胞生成过程中特定差异阶段的基因调节的直接影响。 3）我们将研究破骨细胞对Ankki/Ki小鼠的骨质量表型的贡献。我们的长期目标是研究CMD或类似颅管病患者的骨形成和骨重塑的分子控制机制。这种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的影响，并有望影响CMD和相关疾病的未来治疗。更好地理解骨矿化和控制骨量的机制，对于骨骼形成和吸收不平衡的大部分人群（包括骨质疏松症和骨质疏松症患者）很重要。公共卫生相关性：我们在本申请中提出的问题旨在了解CMD突变对骨骼重塑的后果，并研究在我们的ANK敲入小鼠模型中导致类似CMD的表型的机制。我们希望理解导致CMD的机制将有助于制定这种使人衰弱障碍的治疗干预策略。我们还期望对骨骼重塑领域产生广泛的影响，因为该动物模型的突变会影响骨细胞骨矿化和调节的一些关键机制。