Conditional ablation of Meningioma-1 in osteoblasts

成骨细胞中 Meningioma-1 的条件消融

基本信息

批准号：
8737726
负责人：
PAUL N MACDONALD
金额：
$ 16.84万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-18 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8737726
关键词：
Ablation Address Adult Affect Age Age-Months Aging Aging-Related Process Alleles American Animal Model Area Biology Bone Density Bone Resorption Calcitriol Cell Line Cells Cephalic Coculture Techniques Data Defect Development Disease Endocrine Endocrine system Equilibrium Exons Female Foundations Fracture Future Gender Gene Expression Gene Targeting Genes Genetic Transcription Goals Homeostasis Hormonal Hormones Human Human Resources In Vitro Intestines Knockout Mice Laboratories Ligands Literature Mammals Mediating Metabolic Bone Diseases Minerals Modeling Morbidity - disease rate Morphology Mus Nuclear Nuclear Receptors Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis Ovariectomy Pathway interactions Phenotype Physiological Physiology Prevention Property Proteins Publications Research Research Proposals Research Support Risk Rodent Model Role Site Skeleton Solid Stress System Therapeutic Time Transcription Coactivator Transcriptional Regulation Tumor Suppressor Proteins Vitamin D Vitamin D3 Receptor bone bone loss calcium absorption combat imaging modality in vivo insight intramembranous bone formation long bone male meningioma mineralization mortality mouse model normal aging novel osteoblast differentiation osteoclastogenesis postnatal public health relevance skeletal skeletal disorder spine bone structure substantia spongiosa tibia transcription factor young adult

项目摘要

DESCRIPTION (provided by applicant): The vitamin D receptor (VDR), its requisite hormonal ligand, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), as well as a host of nuclear receptor coactivators and corepressors coordinately control the expression of select genes and gene networks to impact bone by increasing intestinal calcium absorption and by directly affecting osteoblast proliferation, differentiation, and function. Meningioma-1 (MN1) is one such target gene that VDR and 1,25(OH)2D3 regulate in osteoblasts. MN1 is a coactivator of VDR and other nuclear receptors and it is needed for full ligand-induced activity of the VDR. The significance of MN1 in skeletal biology is suggested by the phenotype of the MN1 null mouse model which displays cranial skeletal anomalies in intramembranous ossification. In vitro data support an important role for this novel factor in the osteoblast and in skeletal biology. For example, MN1 is expressed in numerous osteoblastic cell lines including primary osteoblasts, its expression is increased during osteoblast differentiation, MN1 ablation dramatically impacts osteoblast morphology, osteoblast proliferation, osteoblast differentiation, 1,25(OH)2D3-activated gene expression, and 1,25(OH)2D3-stimulated osteoclastogenesis in co-culture studies. However, these in vitro approaches do not address the physiological relevance of MN1 in the postnatal skeleton. Due to postnatal lethality of the global MN1KO model, this critical poin of MN1 biology in the skeleton has remained unaddressed. In this current proposal, we present preliminary data on the development of a new mouse model that addresses this issue. Our laboratory developed a mouse with osteoblast-targeted ablation of the murine MN1 gene using the Col¿1(I)-cre deletor strain combined with a conditional allele in which exon 1 of the murine MN1 gene is flanked by loxP sites. The Col¿1(I)-cre+MN1fl/fl mice displayed a gender-selective and compartment-selective undermineralized skeletal phenotype at 20 weeks of age. These defects are reminiscent of those observed in early bone loss in young adults during the normal aging process in human and rodent models. These new data implicate MN1 in more global skeletal remodeling independent of VDR and the vitamin D endocrine system. This newest model has the potential to uncover new insight into potential mechanisms and biologies involved in early trabecular bone loss in young, adult mammals. Thus, the overall single research goal of this proposal is to characterize the detailed skeletal phenotype of this new model and establish the significance of MN1 in postnatal skeletal physiology.

描述（适用提供）：维生素D受体（VDR），其必要的激素配体，1,25-二羟基维生素D3（1,25（OH）2D3），以及许多核受体共同激活剂和核心力量通过共同控制选择基因和基因的表达来影响核受体共同激活剂和核心，从而促进了基因和基因的表达。成骨细胞增殖，分化和功能。脑膜瘤1（MN1）是一种靶基因，即VDR和1,25（OH）2d3在成骨细胞中调节。 MN1是VDR和其他核接收器的共激活因子，需要全配体诱导的VDR活性。 MN1 NULL小鼠模型的表型提出了MN1在骨骼生物学中的重要性，该模型在膜内骨化中显示颅骨骨骼异常。体外数据支持在成骨细胞和骨骼生物学中这一新因素的重要作用。 For example, MN1 is expressed in numerous osteoblast cell lines including primary osteoblasts, its expression is increased during osteoblast differentiation, MN1 ablation dramatically impacts osteoblast morphology, osteoblast proliferation, osteoblast differentiation, 1,25(OH)2D3-activated gene expression, and 1,25(OH)2D3-stimulated共培养研究中的破骨细胞生成。但是，这些体外方法并不能解决产后骨骼中MN1的生理相关性。由于全球MN1KO模型的产后致死性，骨骼中MN1生物学的这种临界点仍然没有解决。在当前的建议中，我们介绍了有关解决此问题的新鼠标模型的开发的初步数据。我们的实验室使用COL？1（i） - 固定菌株与有条件的等位基因相结合，其中鼠MN1基因的外显子1侧面loxp位点，使用COL�1（i）-CRE菌株与鼠MN1基因进行了成骨细胞的消融小鼠。 COL¿1（I）-CRE+MN1FL/FL小鼠在20周龄时表现出一种性别选择性和隔室选择性的不受欢迎的骨骼表型。这些缺陷让人联想到在人和啮齿动物模型正常衰老过程中年轻人早期骨质流失中观察到的缺陷。这些新数据暗示MN1在更全球的骨骼重塑中，独立于VDR和维生素D内分泌系统。这个最新的模型有可能发现对年轻的成年哺乳动物早期小梁骨质流失的潜在机制和生物的新见解。这就是该提案的总体研究目标是表征该新模型的详细骨骼表型，并确定MN1在产后骨骼生理学中的重要性。