The Role of OPG in GATA-1 Deficiency

OPG 在 GATA-1 缺乏症中的作用

基本信息

批准号：
7673285
负责人：
Melissa A Kacena
金额：
$ 7.4万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7673285
关键词：
Affect Age Albers-Schonberg disease Alkaline Phosphatase Amino Acid Substitution Binding Sites Biochemical Markers Biochemistry Biomechanics Blood Platelets Bone Density Bone Diseases Bone Resorption C-terminal Clinical Cyclophosphamide DNA DNA Binding Data Development Disease Dual-Energy X-Ray Absorptiometry Elderly Event Face Family Family member Foundations Fracture Friends Gene Expression Genetic Screening Goals Hematopoietic Hip Fractures Hip region structure Homeostasis Human Individual Life Link Megakaryocytes Messenger RNA Missense Mutation Morbidity - disease rate Mus Mutation N-terminal Nucleotides Osteocalcin Osteoclasts Osteogenesis Osteoporosis Pain Pathway interactions Patients Peripheral Blood Mononuclear Cell Persons Phenotype Postmenopausal Osteoporosis Prevalence Primary Myelofibrosis Proteins Public Health Quality of life Regulation Regulatory Pathway Research Role Sentinel Serum Skeletal system Source Specimen Spinal Fractures System Testing Therapeutic Thrombasthenia Thrombocytopenia Tumor necrosis factor receptor 11b Type I Procollagen Urine Vertebral column Woman Wrist Zinc Fingers base bone bone cell bone loss bone mass bone turnover clinically significant cofactor experience hip bone human GATA1 protein human disease insight knock-down loss of function mutation mortality mouse model novel therapeutics osteoporosis with pathological fracture peripheral blood prevent promoter sex skeletal therapeutic target thrombocytosis transcription factor translational study

项目摘要

DESCRIPTION (provided by applicant): Osteoporosis is a major public health problem, in which 1 in 2 women over the age of 50 will have an osteoporotic fracture (National Osteoporosis Foundation). Osteoporosis results from an alteration in skeletal homeostasis, whereby bone resorption exceeds formation. We have found that mice deficient in GATA-1, a transcription factor required for normal megakaryocyte development, have a high bone mass phenotype (>3-fold increase in bone volume). This unexpected increase in bone volume speaks to the intimate relationship between the hematopoietic and skeletal system. Recently, 8 families have been identified with GATA-1 missense mutations (loss-of-function mutations) which result in X-linked thrombocytopenia. Affected individuals have a variety of hematologic manifestations which resemble GATA-1 deficient mice. Based on this data it is our hypothesis that mice and humans with GATA-1 loss-of-function mutations have a high bone mass phenotype. Our secondary hypothesis is that osteoprotegerin levels are increased with GATA-1 deficiency and that high osteoprotegerin levels contribute to the high bone mass phenotype. The following Aims will test these hypotheses. In Specific Aim I we will evaluate the bone mineral density in GATA-1 affected, carrier, and control family members using dual energy X-ray absorptiometry. In Specific Aim II we will characterize the biochemical markers of bone turnover in GATA-1 affected, carrier, and control family members. In Specific Aim III we will investigate the osteoclastogenic potential of peripheral blood mononuclear cells from GATA-1 affected, carrier, and control family members. Finally, in Specific Aim IV we will determine whether osteoprotegerin contributes to the high bone mass phenotype seen with GATA-1 deficiency. This translational study will further demonstrate the value of utilizing mouse models to better understand human disease. In addition, this study will show how GATA-1 gene expression correlates with bone turnover and whether osteoprotegerin is responsible for the increased bone mass. Therefore, these studies are relevant to: 1) Megakaryocyte associated diseases, such as thrombocytopenia, thrombocytosis, thrombasthenia, and idiopathic myelofibrosis; 2) Gene expression and human disease; 3) New pathway(s) of bone mass regulation; and 4) Bone loss diseases, such as osteoporosis.

描述（由申请人提供）：骨质疏松症是一个主要的公共卫生问题，其中50岁以上的二分之一的女性将有一个骨质疏松骨折（国家骨质疏松基金会）。骨质疏松症是由于骨骼稳态的改变而导致的，从而骨吸收超过形成。我们发现，缺乏正常巨核细胞发育所需的转录因子GATA-1的小鼠具有较高的骨质量表型（骨体积增加了3倍）。骨体积的意外增加表明造血和骨骼系统之间的亲密关系。最近，已经确定了8个家庭使用GATA-1错义突变（功能丧失突变）这导致X连锁的血小板减少症。受影响的个体具有各种类似于GATA-1缺乏小鼠的血液学表现。基于这些数据，我们的假设是具有GATA-1功能丧失突变的小鼠和人体具有较高的骨质量表型。我们的继发假设是，骨蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白水平因GATA-1缺乏症而增加，而高骨蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白水平有助于高骨质量表型。以下目标将检验这些假设。在特定目的中，我将使用双能X射线吸收仪评估受影响，载体和控制家庭成员的骨矿物质密度。在特定的目标II中，我们将表征受影响，载体和控制家庭成员的骨转换的生化标记。在特定的目标III中，我们将研究受影响，载体和对照家庭成员的外周血单核细胞的破骨细胞生成潜力。最后，在特定的目标IV中，我们将确定骨蛋白蛋白蛋白蛋白是否有助于GATA-1缺乏症看到的高骨质量表型。这项翻译研究将进一步证明利用小鼠模型更好地了解人类疾病的价值。此外，这项研究将显示GATA-1基因表达如何与骨转换以及骨蛋白蛋白蛋白蛋白造成增加的骨骼量相关。因此，这些研究与：1）巨核细胞相关疾病，例如血小板减少症，血小板病，血栓性和特发性骨髓性骨髓纤维化； 2）基因表达和人类疾病； 3）骨骼调节的新途径； 4）骨质流失疾病，例如骨质疏松症。